Phenylglycinamide and pyridylglycinamide derivatives useful as anticoagulants

ABSTRACT

The present invention provides novel phenylglycinamide derivatives of Formula (I) or (IV): 
                         
or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the variables W, W 1 , Y, Z, R 7 , R 8 , R 9 , and R 11  are as defined herein. These compounds are selective inhibitors of factor VIIa which can be used as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the priority benefit of U.S. ProvisionalApplication Ser. No. 60/694,074, filed Jun. 24, 2005 and U.S.Provisional Application Ser. No. 60/694,076, filed Jun. 24, 2005. Theentire disclosure of each of the foregoing applications is hereinincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention provides novel phenylglycinamide andpyridylglycinamide derivatives and analogues thereof, which areselective inhibitors of serine protease enzymes of the coagulationcascade and/or contact activation system; for example factor VIIa,factor Xa, factor XIa, factor IXa, thrombin, and/or plasma kallikrein.In particular, it relates to compounds that are factor VIIa inhibitors.This invention also relates to pharmaceutical compositions comprisingthese compounds and methods of using the same.

BACKGROUND OF THE INVENTION

Factor VIIa is a plasma serine protease involved in the initiation ofthe coagulation cascade. It is present in human blood at a concentrationof approximately 500 ng/mL, with about 1% of the total amount in theproteolytically active form factor VIIa (Morrissey, J. H. et al. Blood1993, 81, 734-744). Factor VIIa binds with high affinity to itscofactor, tissue factor, in the presence of calcium ions to form acomplex with enhanced proteolytic activity (Carson, S. D. and Brozna, J.P. Blood Coag. Fibrinol. 1993, 4, 281-292). Tissue factor is normallyexpressed in cells surrounding the vasculature and within the vesselwall, and is exposed to factor VIIa in blood by vessel injury oratherosclerotic plaque rupture. Once formed, the tissue factor/factorVIIa complex initiates blood coagulation by proteolytic cleavage offactor X to factor Xa, factor IX to factor IXa and autoactivation ofadditional factor VII to VIIa. Factor Xa, generated either directly bytissue factor/factor VIIa or indirectly through action of factor IXa,catalyzes the conversion of prothrombin to thrombin. Thrombin covertsfibrinogen to fibrin, which polymerizes to form the structural frameworkof a blood clot, and activates platelets, which are a key cellularcomponent of coagulation (Hoffman, M. Blood Reviews 2003, 17, S1-S5). Inaddition, there is evidence that tissue factor is present in blood,likely in an encrypted form that is de-encrypted during clot formation.(Giesen, P. L. A. et al. Proc. Natl. Acad. Sci. 1999, 96, 2311-2315;Himber, J. et al. J. Thromb. Haemost. 2003, 1, 889-895). The tissuefactor/factor VIIa complex derived from blood borne tissue factor mayplay an important role in propagation of the coagulation cascade (clotgrowth) and in thrombus formation in the absence of vessel wall injury(i.e., stasis induced deep vein thrombosis or sepsis). The source ofblood borne tissue factor is an area of active research (Morrissey, J.H. J. Thromb. Haemost. 2003, 1, 878-880).

While blood coagulation is essential to the regulation of an organism'shemostasis, it is also involved in many pathological conditions. Inthrombosis, a blood clot, or thrombus, may form and obstruct circulationlocally, causing ischemia and organ damage. Alternatively, in a processknown as embolism, the clot may dislodge and subsequently become trappedin a distal vessel, where it again causes ischemia and organ damage.Diseases arising from pathological thrombus formation are collectivelyreferred to as thrombotic or thromboembolic disorders and include acutecoronary syndrome, unstable angina, myocardial infarction, ischemicstroke, deep vein thrombosis, peripheral occlusive arterial disease,transient ischemic attack, and pulmonary embolism. In addition,thrombosis occurs on artificial surfaces in contact with blood,including catheters and artificial heart valves. Therefore, drugs thatinhibit blood coagulation, or anticoagulants, are “pivotal agents forprevention and treatment of thromboembolic disorders” (Hirsch, J. et al.Blood 2005, 105, 453-463).

Because of its key role in the coagulation cascade, researchers havepostulated that inhibition of factor VIIa could be used to treat orprevent thrombotic or thromboembolic disease. (Girard, T. J.; Nicholson,N. S. Curr. Opin. Pharmacol. 2001, 1, 159-163; Lazarus, R. A., et al.Curr. Med. Chem. 2004, 11, 2275-2290; Frederick, R. et al. Curr. Med.Chem. 2005, 12, 397-417.) Several studies have confirmed that variousbiological and small molecule inhibitors of factor VIIa have in vivoantithrombotic efficacy with a low bleeding liability. For instance, ithas been demonstrated that a biological factor VIIa inhibitor XK1,comprising a hybrid of Factor X light chain and tissue factor pathwayinhibitor first kunitz domain, prevents thrombus formation in a ratmodel of arterial thrombosis, with no change in bleeding time or totalblood loss (Szalony, J. A. et al. J. Thrombosis and Thrombolysis 2002,14, 113-121). In addition, small molecule active site directed factorVIIa inhibitors have demonstrated antithrombotic efficacy in animalmodels of arterial thrombosis (Suleymanov, O., et al. J Pharmacology andExperimental Therapeutics 2003, 306, 1115-1121; Young, W. B., et al.Bioorg. Med. Chem. Lett. 2006, 16, 2037-2041) and venous thrombosis(Szalony, J. A., et al. Thrombosis Research 2003, 112, 167-174; Arnold,C. S., et al. Thrombosis Research 2006, 117, 343-349), with littleimpact on bleeding time or blood loss. Moreover, the biological factorVIIa inhibitor recombinant nematode anticoagulant protein c2 (rNAPc2) iscurrently under clinical investigation for treatment of acute coronarysyndromes. Results of initial clinical trials demonstrate that rNAPc2reduces systemic thrombin generation in patients undergoing coronaryangioplasty (Moons, A. H. M. J. Am. Coll. Cardiol. 2003, 41, 2147-2153)and that it prevents deep vein thrombosis in patients undergoing totalknee replacement (Lee, A., et al. Circulation 2001, 104, 74-78).

Work has accordingly been performed to identify and optimize factor VIIainhibitors. For example, U.S. Pat. No. 5,866,542 describes recombinantnematode anticoagulant proteins which inhibit factor VIIa. U.S. Pat. No.5,843,442 discloses monoclonal antibodies or antibody fragmentspossessing factor VIIa inhibitory activity, and U.S. Pat. No. 5,023,236presents tripeptides and tripeptide derivatives that inhibit factorVIIa.

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces (e.g., during hemodialysis, ‘on-pump’cardiovascular surgery, vessel grafts, bacterial sepsis). This processis also termed contact activation. Surface absorption of factor XIIleads to a conformational change in the factor XII molecule, therebyfacilitating activation to proteolytically active factor XII (factorXIIa and factor XIIf). Factor XIIa (or XIIf) has a number of targetproteins, including plasma prekallikrein and factor XI. Active plasmakallikrein further activates factor XII, leading to an amplification ofcontact activation. Activated FXI acts on FIX, which acts through thecoagulation cascade to produce thrombin. Thus, inhibitors of plasmakallikrein would be expected to exert an antithrombotic effect underconditions of contact activation. Contact activation is a surfacemediated process responsible in part for the regulation of thrombosisand inflammation, and is mediated, at least in part, by fibrinolytic-,complement-, kininogen/kinin-, and other humoral and cellular pathways(for review, Coleman, R. Contact Activation Pathway, pages 103-122 inHemostasis and Thrombosis, Lippincott Williams & Wilkins 2001; SchmaierA. H. Contact Activation, pages 105-128 in Thrombosis and Hemorrhage,1998).

Plasma kallikrein is a zymogen of a trypsin-like serine protease and ispresent in plasma at 35 to 50 μg/mL. The gene structure is similar tothat of factor XI; overall, the amino acid sequence of plasma kallikreinhas 58% homology to factor XI. Proteolytic activation by factor XIIa atan internal 1389-R390 bond yields a heavy chain (371 amino acids) and alight chain (248 amino acids). The active site of kallikrein iscontained in the light chain. The light chain of plasma kallikreinreacts with protease inhibitors, including alpha 2 macroglobulin andC1-inhibitor. Interestingly, heparin significantly accelerates theinhibition of plasma kallikrein by antithrombin III in the presence ofhigh molecular weight kininogen (HMWK). In blood, the majority of plasmakallikrein circulates in complex with HMWK. Kallikrein cleaves HMWK toliberate bradykinin. Bradykinin release results in increase of vascularpermeability and vasodilation (for review, Coleman, R. ContactActivation Pathway, pages 103-122 in Hemostasis and Thrombosis,Lippincott Williams & Wilkins 2001; Schmaier A. H. Contact Activation,pages 105-128 in Thrombosis and Hemorrhage, 1998). Inhibitors of plasmakallikrein would be expected to reduce potential for bradykinin releaseand thus to exert an anti-inflammatory effect.

While a number of factor VIIa inhibitors have been discussed in the art,improved inhibitors, especially non-peptide inhibitors, of serineproteases for the treatment of thromboembolic disorders are alwaysdesirable. The present invention discloses phenylglycinamide andpyridylglycinamide derivatives and analogues thereof, as inhibitors ofcoagulation Factor VIIa and, as such, their utility in the treatment ofthromboembolic disorders.

In addition, it is also desirable to find new compounds with improvedpharmacological characteristics compared with known serine proteaseinhibitors. For example, it is preferred to find new compounds withimproved factor VIIa inhibitory activity and selectivity for factor VIIaversus other serine proteases. Also, it is preferred to find newcompounds with improved plasma kallikrein inhibitory activity andselectivity for plasma kallikrein versus other serine proteases. Also,it is preferred to find new compounds with improved activity in in vitroclotting assays, such as the prothrombin time (PT) assay or activatedpartial thromboplastin time assay (APTT) (for a description of the PTand APTT assays see, Goodnight, S. H.; Hathaway, W. E. Screening Testsof Hemostasis. Disorders of Thrombosis and Hemostasis: a clinical guide,2^(nd) edition, McGraw-Hill: New York, 2001 pp. 41-51). It is alsodesirable and preferable to find compounds with advantageous andimproved characteristics in one or more of the following categories,which are given as examples and are not intended to be limiting: (a)pharmacokinetic properties, including oral bioavailability; (b)pharmaceutical properties; (c) dosage requirements; (d) factors whichdecrease blood concentration peak-to-trough characteristics; (e) factorsthat increase the concentration of active drug at the receptor; (f)factors that decrease the liability for clinical drug-drug interactions;(g) factors that decrease the potential for adverse side-effects; and,(h) factors that improve manufacturing costs or feasibility.

SUMMARY OF THE INVENTION

The present invention provides novel phenylglycinamide andpyridylglycinamide derivatives, and analogues thereof, which are usefulas selective inhibitors of serine protease enzymes, especially factorVIIa, including stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

The present invention also provides processes and intermediates formaking one of the compounds of the present invention or a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate, or prodrug thereof.

The present invention also provides a method for modulation of thecoagulation cascade and/or the contact activation system comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a stereoisomer, tautomer, pharmaceutically acceptable salt,solvate, or prodrug thereof.

The present invention also provides a method for treating a thromboticor thromboembolic disorder comprising administering to a patient in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate, or prodrug thereof.

The present invention also provides a method for treating inflammatorydisorders comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, tautomer, pharmaceuticallyacceptable salt or prodrug thereof.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment of a thrombotic or thromboembolicdisorder.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment of an inflammatory disorder.

These and other features of the invention will be set forth in theexpanded form as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides, inter alia,compounds of Formula (I):

or a stereoisomer or pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein:

W is substituted with 0-2 R⁶ and selected from:

X is CH, CR⁶ or N;

Y is selected from:

R¹ is independently at each occurrence, H, F, Cl, Br, I, C₁₋₄ alkylsubstituted with 0-1 OH, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ haloalkyl, —O—C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl;

R² and R³ are, independently at each occurrence, selected from: H, F,Cl, Br, I, OR^(a), SR^(e), OCF₃, OCHF₂, OCH₂F, CN, NO₂, —NR^(c)R^(d),—C(O)R^(a), —CO₂R^(a), —NR^(c)C(O)R^(a), —C(O)NR^(c)R^(d),—NR^(c)C(O)OR^(e), —NR^(c)C(O)NR^(c)R^(d), —OC(O)NR^(c)R^(d),—SO₂NR^(c)R^(d), —NR^(c)SO₂NR^(c)R^(d), —NR^(c)SO₂R^(e), —NR^(c)SO₂CF₃,—SO₂CF₃, —S(O)₂R^(e), C₁₋₄ alkyl substituted with 0-2 R^(f, C) ₂₋₄alkenyl substituted with 0-2 R^(f), and C₂₋₄ alkynyl substituted with0-2 R^(f);

R⁴ is, independently at each occurrence, H, F, Cl, Br, I, OR^(a),SR^(e), OCF₃, OCHF₂, OCH₂F, CN, NO₂, —NR^(c)R^(d), —C(O)R^(a),—CO₂R^(a), —NR^(c)C(O)R^(a), —C(O)NR^(c)R^(d), —NR^(c)C(O)OR^(e),—NR^(c)C(O)NR^(c)R^(d), —OC(O)NR^(c)R^(d), —SO₂NR^(c)R^(d),—NR^(c)SO₂NR^(c)R^(d), —NR^(c)SO₂R^(e), —NR^(c)SO₂CF₃, —SO₂CF₃,—S(O)₂R^(e), —OCH₂CO₂R^(a), —O(benzyl substituted with CO₂R^(a)),tetrazolyl, —SO₂NHCOR^(a), —CONHSO₂R^(e), C₁₋₄ alkyl substituted with0-2 R^(f), C₂₋₄ alkenyl substituted with 0-2 R^(f), or C₂₋₄ alkynylsubstituted with 0-2 R^(f);

alternatively, R² and R³ may combine to form a 5- to 7-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-4 heteroatomsselected from N, NR^(c), O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 0-3 R^(f);

alternatively, R³ and R⁴ may combine to form a 5- to 7-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-4 heteroatomsselected from N, NR^(c), O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 0-3 R^(f);

R⁶ is, independently at each occurrence, F, Cl, Br, C₁₋₃ alkyl, or C₁₋₃alkoxy;

R⁷ is H, C₁₋₄ alkyl, —CH₂CO₂R^(a), —CH₂CH₂CO₂R^(a), —CH₂CH₂OH,—CH₂CH₂CH₂OH, tetrazolyl, —CH₂CONHSO₂R^(e), or —CH₂CH₂CONHSO₂R^(e);

R⁸ is H, C₁₋₄ alkyl, CO₂R^(a), —CH₂CO₂R^(a), —CH₂OH, —CH₂CH₂OH,tetrazolyl, —CONHSO₂R^(e), or —CH₂CONHSO₂R^(e);

R⁹ is H or C₁₋₄ alkyl;

alternatively, R⁸ and R⁹ can be taken together with the carbon atom towhich they are attached to form a 3- to 5-membered carbocycle;

Z is phenyl substituted with 0-3 R¹⁰ or pyridyl substituted with 0-3R¹⁰;

R¹⁰ is, independently at each occurrence, F, Cl, Br, CN, CH₂F, CHF₂,CF₃, OCF₃, SCF₃, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, —(CH₂)_(n)—OR^(a),SR^(e), —(CH₂)_(n)—NR^(c)R^(d), CO₂R^(a), CONR^(c)R^(d), —SO₂R^(e),—SO₂NR^(c)R^(d), —NR^(h)COR^(a), —NR^(h)CO₂R^(a), —NR^(h)CONR^(c)R^(d),—OC(O)NR^(c)R^(d), —SO₂NR^(c)R^(d), —OSO₂NR^(c)R^(d),—NR^(h)SO₂NR^(c)R^(d), —NR^(h)SO₂R^(e), —B(OH)₂, —(CH₂)_(n)-phenyl,—NH-phenyl, —NH(-5- to 6-membered heteroaryl comprising: carbon atomsand 1-3 heteroatoms selected from N, O, and S(O)_(p)), or —(CH₂)_(n)-5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said phenyl, heteroaryl andheterocycle are substituted with 0-3 R^(i);

alternatively, when two R¹⁰ groups are substituted on adjacent ringatoms, they can be taken together with the ring atoms to which they areattached to form a 5- to 7-membered carbocycle or heterocyclecomprising: carbon atoms and 0-4 heteroatoms selected from N, O, andS(O)_(p), wherein said carbocycle or heterocycle is substituted with 0-2R^(i);

R¹¹ is H or C₁₋₃ alkyl;

R^(a) is, independently at each occurrence, H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, phenyl, or benzyl; wherein said alkyl, cycloalkyl, phenyland benzyl are optionally substituted with 0-2 R^(f);

R^(c) and R^(d) are, independently at each occurrence, H, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, phenyl, or benzyl;

alternatively, R^(c) and R^(d), when attached to the same nitrogen atom,combine to form a 3- to 7-membered heterocycle comprising: carbon atomsand 0-2 additional heteroatoms selected from N, O, and S(O)_(p); whereinsaid heterocycle is substituted with 0-2 R^(g);

R^(e) is, independently at each occurrence, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,phenyl, or benzyl;

R^(f) is, independently at each occurrence, F, CF₃, OH, C₁₋₃ alkoxy, orC₃₋₆ cycloalkyl;

R^(g) is, independently at each occurrence, ═O, F, Cl, Br, CF₃, OH, orC₁₋₄ alkyl;

R^(h) is, independently at each occurrence, H or C₁₋₃ alkyl;

R^(i) is, independently at each occurrence, F, Cl, Br, CF₃, OH, or C₁₋₄alkyl;

n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and

p, at each occurrence, is selected from 0, 1, and 2;

provided that when R⁸ and R⁹ are both H, then Z is other thanunsubstituted phenyl.

In a second embodiment, the present invention includes the compounds ofFormula (I), within the scope of the first embodiment wherein:

R¹ is F, Cl, Br, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio,C₃₋₆ cycloalkyl, OCF₃, OCHF₂, or OCH₂F;

R² and R³ are, independently at each occurrence, selected from: H, F,Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OCHF₂, or OCH₂F;

R⁴ is, independently at each occurrence, H, F, Cl, Br, C₁₋₄ alkyl, orC₁₋₄ alkoxy;

R⁶ is, independently at each occurrence, F, Cl, Me or OMe;

R⁷ is H, C₁₋₄ alkyl, or —CH₂CO₂R^(a); and

R⁸ is H, C₁₋₄ alkyl, CO₂R^(a), or —CH₂CO₂R^(a);

provided that when R⁸ and R⁹ are both H, then Z is other thanunsubstituted phenyl.

In some embodiments, the present invention includes compounds of Formula(I) wherein: W is substituted with 0-2 R⁶ and selected from:

In other embodiments, the present invention includes compounds ofFormula (I) wherein: W is

substituted with 0-2 R⁶.

In some embodiments, the present invention includes compounds of Formula(I) wherein: X is CH.

In some embodiments, the present invention includes compounds of Formula(I) wherein: Y is:

In some embodiments, the present invention includes compounds of Formula(I) wherein: Y is selected from:

In some embodiments, the present invention includes compounds of Formula(I) wherein: R¹ is F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCHF₂, orcyclopropyl. In other embodiments, the present invention includescompounds of Formula (I) wherein: R¹ is F, Cl, Br, Me, Et, Pr, i-Pr,vinyl, 2-propenyl, allyl, OMe, OEt, OPr, OCHF₂, SMe, SEt, orcyclopropyl. In other embodiments, the present invention includescompounds of Formula (I) wherein: R¹ is Cl, Br, Me, Et, Pr, i-Pr, vinyl,2-propenyl, OMe, OEt, OPr, OCHF₂, or cyclopropyl. In other embodiments,the present invention includes compounds of Formula (I) wherein: R¹ isCl, Br, Me, Et, OMe, OEt, OPr, OCHF₂, or cyclopropyl. In otherembodiments, the present invention includes compounds of Formula (I)wherein: R¹ is OMe or OEt.

In some embodiments, the present invention includes compounds of Formula(I) wherein: R² is H, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, or OCHF₂. Inother embodiments, the present invention includes compounds of Formula(I) wherein: R² is H, F, Cl, Br, C₁₋₄ alkoxy, or OCHF₂. In otherembodiments, the present invention includes compounds of Formula (I)wherein: R² is H, F, Cl, OMe, O(i-Pr), or OCHF₂. In other embodiments,the present invention includes compounds of Formula (I) wherein: R² isH, OMe, or O(i-Pr).

In some embodiments, the present invention includes compounds of Formula(I) wherein: R³ is H, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, or OCHF₂. Inother embodiments, the present invention includes compounds of Formula(I) wherein: R³⁻ is H or C₁₋₄ alkoxy. In other embodiments, the presentinvention includes compounds of Formula (I) wherein: R³ is H.

In some embodiments, the present invention includes compounds of Formula(I) wherein: R⁴ is H, F, Cl, Br, C₁₋₄ alkyl, or C₁₋₄ alkoxy. In otherembodiments, the present invention includes compounds of Formula (I)wherein: R⁴ is H, F, Cl, or C₁₋₃ alkoxy. In other embodiments, thepresent invention includes compounds of Formula (I) wherein: R⁴ is H, F,Cl, or OMe.

In some embodiments, the present invention includes compounds of Formula(I) wherein: R⁶ is, independently at each occurrence, F, Cl, Me or OMe.In other embodiments, the present invention includes compounds ofFormula (I) wherein: R⁶ is, independently at each occurrence, F, Cl, orMe.

In some embodiments, the present invention includes compounds of Formula(I) wherein: R⁷ is H, Me, —CH₂CO₂H, —CH₂CO₂Me, or —CH₂CO₂Et. In otherembodiments, the present invention includes compounds of Formula (I)wherein: R⁷ is H or Me.

In some embodiments, the present invention includes compounds of Formula(I) wherein: R⁸ is H, Me, CO₂H, CO₂Me, CO₂Et, —CH₂CO₂H, —CH₂CO₂Me, or—CH₂CO₂Et. In other embodiments, the present invention includescompounds of Formula (I) wherein: R⁸ is H or Me.

In some embodiments, the present invention includes compounds of Formula(I) wherein: R⁹ is H.

In some embodiments, the present invention includes compounds of Formula(I) wherein: R¹⁰ is, independently at each occurrence, F, Cl, Br, CF₃,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, OR^(a), SR^(e), NR^(c)R^(d),—CH₂NR^(c)R^(d), CONR^(c)R^(d), —SO₂R^(e), —SO₂NR^(c)R^(d), —NHCOR^(a),—NHCO₂R^(a), —NHCONR^(c)R^(d), —OSO₂NR^(c)R^(d), —NHSO₂NR^(c)R^(d),—NHSO₂R^(e), —B(OH)₂, phenyl substituted with 0-2 R^(i), or a 5- to6-membered heterocycle substituted with 0-2 R^(i) and selected from:morpholinyl, piperidyl, pyrazolyl, and triazolyl. In other embodiments,the present invention includes compounds of Formula (I) wherein: R¹⁰ is,independently at each occurrence, F, Cl, Br, C₁₋₄ alkyl, C₂₋₄ alkenyl,OR^(a), SR^(e), NR^(c)R^(d), —CH₂NR^(c)R^(d), CONR^(c)R^(d), —SO₂R^(e),—SO₂NR^(c)R^(d), —NHCOR^(a), —NHCO₂R^(a), —NHCONR^(c)R^(d),—OSO₂NR^(c)R^(d), —NHSO₂NR^(c)R^(d), —NHSO₂R^(e), morpholin-4-yl,piperid-1-yl, 3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl. Inother embodiments, the present invention includes compounds of Formula(I) wherein: R¹⁰ is, independently at each occurrence, CONR^(c)R^(d),—SO₂R^(e), —SO₂NR^(c)R^(d), —NHCOR^(a), —NHCO₂R^(a), —NHCONR^(c)R^(d),—OSO₂NR^(c)R^(d), —NHSO₂NR^(c)R^(d), or —NHSO₂R^(e).

In some embodiments, the present invention includes compounds of Formula(I) wherein: R¹¹ is H.

In some embodiments, the present invention includes compounds of Formula(I) wherein: Z is phenyl substituted with 0-3 R¹⁰.

In a third embodiment, the present invention includes the compounds ofFormula (II):

or a stereoisomer or pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein:

W is substituted with 0-1 R⁶ and selected from:

X¹ is CH or N;

X² is CH or N;

X³ is CR^(10c) or N;

provided that only one of X¹, X² and X³ may be N;

R¹ is H, F, Cl, Br, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₃₋₆ cycloalkyl, OCF₃, OCHF₂, or OCH₂F;

R² and R³ are independently selected from: H, F, Cl, Br, I, OR^(a),SR^(e), OCF₃, OCHF₂, OCH₂F, CN, NO₂, —NR^(c)R^(d), —C(O)R^(a),—CO₂R^(a), —NR^(c)C(O)R^(a), —C(O)NR^(c)R^(d), —NR^(c)C(O)OR^(e),—NR^(c)C(O)NR^(c)R^(d), —OC(O)NR^(c)R^(d), —SO₂NR^(c)R^(d),—NR^(c)SO₂NR^(c)R^(d), —NR^(c)SO₂R^(e), —NR^(c)SO₂CF₃, —SO₂CF₃,—S(O)₂R^(e), C₁₋₄ alkyl substituted with 0-2 R^(f), C₂₋₄ alkenylsubstituted with 0-2 R^(f), and C₂₋₄ alkynyl substituted with 0-2 R^(f);

R⁴ is H, F, Cl, Br, I, OR^(a), SR^(e), OCF₃, CN, NO₂, —NR^(c)R^(d),—C(O)R^(a), —CO₂R^(a), —NR^(c)C(O)R^(a), —C(O)NR^(c)R^(d),—NR^(c)C(O)OR^(e), —NR^(c)C(O)NR^(c)R^(d), —OC(O)NR^(c)R^(d),—SO₂NR^(c)R^(d), —NR^(c)SO₂NR^(c)R^(d), —NR^(c)SO₂R^(e), —NR^(c)SO₂CF₃,—SO₂CF₃, —S(O)₂R^(e), —OCH₂CO₂R^(a), —O(benzyl substituted withCO₂R^(a)), tetrazolyl, SO₂NHCOR^(a), —CONHSO₂R^(e), C₁₋₄ alkylsubstituted with 0-2 R^(f), C₂₋₄ alkenyl substituted with 0-2 R^(f),C₂₋₄ alkynyl substituted with 0-2 R^(f);

alternatively, R² and R³ may combine to form a 5- to 6-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-3 heteroatomsselected from N, NR^(c), O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 0-3 R^(f);

R⁶ is, independently at each occurrence, F, Cl, Br, C₁₋₃ alkoxy or C₁₋₃alkyl;

R⁷ is H, C₁₋₄ alkyl, —CH₂CO₂R^(a), —CH₂CH₂CO₂R^(a), —CH₂CH₂OH,—CH₂CH₂CH₂OH, tetrazolyl, —CH₂CONHSO₂R^(e), or —CH₂CH₂CONHSO₂R^(e);

R⁸ is H, C₁₋₄ alkyl, CO₂R^(a), —CH₂CO₂R^(a), —CH₂OH, —CH₂CH₂OH,tetrazolyl, —CONHSO₂R^(e), or —CH₂CONHSO₂R^(e);

R⁹ is H or Me;

alternatively, R⁸ and R⁹ can be taken together with the carbon atom towhich they are attached to form a 3- to 5-membered carbocycle;

R^(10a) is H, F, Cl, Br, CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, OR^(a), SR^(e),NR^(c)R^(d), CONR^(c)R^(d), —SO₂R^(e), —SO₂NR^(c)R^(d), phenylsubstituted with 0-2 R^(i), or a 5- to 6-membered heterocyclesubstituted with 0-2 R^(i) and selected from: morpholinyl, piperidyl,pyrazolyl, and triazolyl;

R^(10b) is H, OR^(a), NR^(c)R^(d), —NHCOR^(a), —NHCO₂R^(a),—NHCONR^(c)R^(d), —SO₂NR^(c)R^(d), —OSO₂NR^(c)R^(d), —NHSO₂NR^(c)R^(d),—NHSO₂R^(e), —B(OH)₂, —NH(-5 to 6-membered heteroaryl comprising: carbonatoms and 1-3 heteroatoms selected from N, O, and S(O)_(p) andsubstituted with 0-2 R^(i)), —NH-phenyl substituted with 0-2 R^(i), or a5-membered heterocycle substituted with 0-2 R^(i) and selected from:tetrazolyl, pyrazolyl, pyrrolyl, and triazolyl;

R^(10c) is H, F, Cl, Br, CF₃, C₁₋₆ alkyl, OR^(a), SR^(e), orNR^(c)R^(d);

R¹¹ is H;

R^(a) is, independently at each occurrence, H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, phenyl, or benzyl; wherein said alkyl, cycloalkyl, phenyland benzyl are optionally substituted with 0-2 R^(f);

R^(c) and R^(d) are, independently at each occurrence, H, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, phenyl, or benzyl;

alternatively, R^(c) and R^(d), when attached to the same nitrogen atom,combine to form a 4- to 7-membered heterocycle comprising: carbon atomsand 0-2 additional heteroatoms selected from N, O, and S(O)_(p); whereinsaid heterocycle is substituted with 0-2 R^(g);

R^(e) is, independently at each occurrence, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,phenyl, or benzyl;

R^(f) is, independently at each occurrence, F, CF₃, OH, C₁₋₃ alkoxy, orC₃₋₆ cycloalkyl;

R^(g) is, independently at each occurrence, ═O, F, Cl, Br, CF₃, OH, orC₁₋₄ alkyl;

R^(i) is, independently at each occurrence, F, Cl, Br, CF₃, OH, or C₁₋₄alkyl;

n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and

p, at each occurrence, is selected from 0, 1, and 2;

provided that when R⁸ and R⁹ are both H, X¹, X², and X³ are CH, andR^(10a) is H, then R^(10b) is other than H.

In a fourth embodiment, the present invention includes the compounds ofFormula (II), within the scope of the third embodiment wherein:

R¹ is F, Cl, Br, Me, Et, Pr, i-Pr, vinyl, 2-propenyl, allyl, OMe, OEt,OPr, OCHF₂, SMe, SEt, or cyclopropyl;

R² and R³ are independently selected from: H, F, Cl, Br, C₁₋₄ alkyl,C₁₋₄ alkoxy, or OCHF₂;

alternatively, R² and R³ may combine to form a 5- to 6-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-3 heteroatomsselected from N, NR^(c), O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 0-3 R^(f);

R⁴ is H, F, Cl, Br, C₁₋₄ alkyl, or C₁₋₄ alkoxy;

R⁶ is, independently at each occurrence, F, Cl, Me or OMe;

R⁷ is H, C₁₋₄ alkyl, or —CH₂CO₂R^(a);

R⁸ is H, C₁₋₄ alkyl, CO₂R^(a), or —CH₂CO₂R^(a);

R⁹ is H; and

R^(10c) is H, F, Cl, Br, C₁₋₄ alkyl, or NR^(c)R^(d);

provided that when R⁸ is H, X¹, X², and X³ are CH, and R^(10a) is H,then R^(10b) is other than H.

In a fifth embodiment, the present invention includes the compounds ofFormula (II), within the scope of the third embodiment wherein:

R¹ is Cl, Br, Me, Et, vinyl, 2-propenyl, OMe, OEt, OPr, OCHF₂, orcyclopropyl;

R² is H, F, Cl, Br, C₁₋₄ alkoxy, or OCHF₂;

R³ is H or C₁₋₄ alkoxy;

alternatively, R² and R³ may combine to form a 5- to 6-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-3 heteroatomsselected from N, NR^(c), O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 0-3 R^(f);

R⁴ is H, F, Cl, or C₁₋₃ alkoxy;

R⁶ is, independently at each occurrence, F, Cl, or Me;

R⁷ is H, C₁₋₄ alkyl, or —CH₂CO₂R^(a);

R⁸ is H, C₁₋₄ alkyl, CO₂R^(a), or —CH₂CO₂R^(a);

R⁹ is H;

R^(10a) is H, F, Cl, Br, C₁₋₄ alkyl, C₂₋₄ alkenyl, OR^(a), SR^(e),CONR^(c)R^(d), —SO₂R^(e), —SO₂NR^(c)R^(d), morpholin-4-yl, piperid-1-yl,3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl;

R^(10b) is H, OH, NHR^(c), —NHCOR^(a), —NHCO₂R^(a), —NHCONR^(c)R^(d),—SO₂NHR^(c), —OSO₂NHR^(c), —NHSO₂NR^(c)R^(d), or —NHSO₂R^(e);

R^(10c) is H, Cl, or Me;

R^(a) is, independently at each occurrence, H, C₁₋₄ alkyl, or C₃₋₆cycloalkyl;

R^(c) and R^(d) are, independently at each occurrence, H, C₁₋₄ alkyl orC₃₋₆ cycloalkyl;

alternatively, R^(c) and R^(d), when attached to the same nitrogen atom,combine to form a 4- to 7-membered heterocycle comprising: carbon atomsand 0-2 additional heteroatoms selected from N, O, and S(O)_(p); whereinsaid heterocycle is substituted with 0-2 R^(g); and

R^(e) is C₁₋₄ alkyl or C₃₋₆ cycloalkyl;

provided that when R⁸ is H, X¹, X², and X³ are CH, and R^(10a) is H,then R^(10b) is other than H; additionally, provided that any two of R²,R⁸, R^(10a), and R^(10b) are other than H.

In a sixth embodiment, the present invention includes the compounds ofFormula (II), within the scope of the third embodiment wherein:

W is selected from:

R¹ is Cl, Br, Me, Et, OMe, OEt, OPr, OCHF₂, or cyclopropyl;

R² is H, F, Cl, OMe, O(i-Pr), or OCHF₂;

R³ is H or OMe;

alternatively, R² and R³ may combine to form a 5-membered heterocyclecomprising: carbon atoms and 1-3 heteroatoms selected from N, NR^(c), O,and S(O)_(p), wherein said heterocycle is substituted with 0-3 R^(f);

R⁴ is H, F, Cl, or OMe;

R⁷ is H, Me, —CH₂CO₂H, or —CH₂CO₂(C₁₋₄ alkyl);

R⁸ is H, Me, CO₂H, CO₂(C₁₋₄ alkyl), —CH₂CO₂H, or —CH₂CO₂(C₁₋₄ alkyl);

R⁹ is H;

R^(10a) is H, F, O(C₁₋₄ alkyl), CONR^(c)R^(d), —S(C₁₋₄ alkyl), —SO₂(C₁₋₄alkyl), —SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl, —SO₂—(pyrrolidin-1-yl), —SO₂— (piperid-1-yl), —SO₂-(azepan-1-yl),—SO₂NR^(c)R^(d), —SO₂NH-cyclopropyl, morpholin-4-yl,3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl;

R^(10b) is H, OH, NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂NH₂,—SO₂NH₂, or —NHCONR^(c)R^(d);

R^(10c) is H, F, Cl, or Me;

R^(c) and R^(d) are, independently at each occurrence, H or C₁₋₄ alkyl;

alternatively, R^(c) and R^(d), when attached to the same nitrogen atom,combine to form a 4- to 5-membered heterocycle comprising: carbon atomsand 0-2 additional heteroatoms selected from N, O, and S(O)_(p); whereinsaid heterocycle is substituted with 0-2 R^(g); and

R^(g) is, independently at each occurrence, ═O, F, Cl, Br, CF₃, OH, orC₁₋₄ alkyl;

provided that when R⁸ is H, X¹, X², and X³ are CH, and R^(10a) is H,then R^(10b) is other than H; additionally, provided that any two of R²,R⁸, R^(10a), and R^(10b) are other than H.

In some embodiments, the present invention includes compounds of Formula(I) wherein: W is

substituted with 0-1 R⁶.

In some embodiments, the present invention includes compounds of Formula(II) wherein: X¹ is CH.

In some embodiments, the present invention includes compounds of Formula(II) wherein: X² is CH.

In some embodiments, the present invention includes compounds of Formula(II) wherein: X³ is CR^(10c). In other embodiments, the presentinvention includes compounds of Formula (II) wherein: X³ is CH.

In some embodiments, the present invention includes compounds of Formula(II) wherein: R¹ is F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCHF₂, orcyclopropyl. In other embodiments, the present invention includescompounds of Formula (II) wherein: R¹ is F, Cl, Br, Me, Et, Pr, i-Pr,vinyl, 2-propenyl, allyl, OMe, OEt, OPr, OCHF₂, SMe, SEt, orcyclopropyl. In other embodiments, the present invention includescompounds of Formula (II) wherein: R¹ is Cl, Br, Me, Et, Pr, i-Pr,vinyl, 2-propenyl, OMe, OEt, OPr, OCHF₂, or cyclopropyl. In otherembodiments, the present invention includes compounds of Formula (II)wherein: R¹ is Cl, Br, Me, Et, OMe, OEt, OPr, OCHF₂, or cyclopropyl. Inother embodiments, the present invention includes compounds of Formula(II) wherein: R¹ is OMe or OEt.

In some embodiments, the present invention includes compounds of Formula(II) wherein: R² is H, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, or OCHF₂. Inother embodiments, the present invention includes compounds of Formula(II) wherein: R² is H, F, Cl, Br, C₁₋₄ alkoxy, or OCHF₂. In otherembodiments, the present invention includes compounds of Formula (II)wherein: R² is H, F, Cl, OMe, O(i-Pr), or OCHF₂. In other embodiments,the present invention includes compounds of Formula (II) wherein: R² isH, OMe, or O(i-Pr).

In some embodiments, the present invention includes compounds of Formula(II) wherein: R³ is H, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, or OCHF₂. Inother embodiments, the present invention includes compounds of Formula(II) wherein: R³ is H or C₁₋₄ alkoxy. In other embodiments, the presentinvention includes compounds of Formula (II) wherein: R³ is H.

In some embodiments, the present invention includes compounds of Formula(II) wherein: R⁴ is H, F, Cl, Br, C₁₋₄ alkyl, or C₁₋₄ alkoxy. In otherembodiments, the present invention includes compounds of Formula (II)wherein: R⁴ is H, F, Cl, or C₁₋₃ alkoxy. In other embodiments, thepresent invention includes compounds of Formula (II) wherein: R⁴ is H,F, Cl, or OMe.

In some embodiments, the present invention includes compounds of Formula(II) wherein: R⁶ is, independently at each occurrence, F, Cl, Me or OMe.In other embodiments, the present invention includes compounds ofFormula (II) wherein: R⁶ is, independently at each occurrence, F, Cl, orMe. In other embodiments, the present invention includes compounds ofFormula (II) wherein: R⁶ is, independently at each occurrence, F or Me.

In some embodiments, the present invention includes compounds of Formula(II) wherein: R⁷ is H, Me, —CH₂CO₂H, —CH₂CO₂Me, or —CH₂CO₂Et. In otherembodiments, the present invention includes compounds of Formula (II)wherein: R⁷ is H or Me.

In some embodiments, the present invention includes compounds of Formula(II) wherein: R⁸ is H, Me, CO₂H, CO₂Me, CO₂Et, —CH₂CO₂H, —CH₂CO₂Me, or—CH₂CO₂Et. In other embodiments, the present invention includescompounds of Formula (II) wherein: R⁸ is H or Me.

In some embodiments, the present invention includes compounds of Formula(II) wherein: R⁹ is H.

In some embodiments, the present invention includes compounds of Formula(II) wherein: R^(10a) is H, F, Cl, Br, C₁₋₄ alkyl, C₂₋₄ alkenyl, OR^(a),SR^(e), CONR^(c)R^(d), —SO₂R^(e), —SO₂NR^(c)R^(d), morpholin-4-yl,piperid-1-yl, 3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl. Inother embodiments, the present invention includes compounds of Formula(II) wherein: R^(10a) is H, F, i-Bu, —CH═C(Me)₂, O(C₁₋₄ alkyl),CONR^(c)R^(d), —S(C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl), —SO₂-cyclopropyl,—SO₂-cyclobutyl, —SO₂-cyclopentyl, —SO₂— (pyrrolidin-1-yl), —SO₂—(piperid-1-yl), —SO₂-(azepan-1-yl), —SO₂NR^(c)R^(d), —SO₂NH-cyclopropyl,morpholin-4-yl, 3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl.In other embodiments, the present invention includes compounds ofFormula (II) wherein:

-   -   R^(10a) is H, F, O(i-Pr), CONMe₂, CONEt₂, CON(Me)Et,        —CO-(pyrrolidin-1-yl), —CO-(piperid-1-yl), —S(i-Pr), —SO₂Et,        —SO₂Pr, —SO₂(i-Pr), —SO₂(t-Bu), —SO₂-cyclopropyl,        —SO₂-cyclobutyl, —SO₂-cyclopentyl, —SO₂-(pyrrolidin-1-yl), —SO₂—        (piperid-1-yl), —SO₂-(azepan-1-yl), —SO₂NHMe, —SO₂NMe₂,        —SO₂NHEt, —SO₂NH(i-Pr), —SO₂NH-cyclopropyl, morpholin-4-yl,        3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl. In other        embodiments, the present invention includes compounds of        Formula (II) wherein: R^(10a) is —SO₂Et, —SO₂Pr, —SO₂(i-Pr),        —SO₂(t-Bu), —SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl,        —SO₂— (pyrrolidin-1-yl), —SO₂— (piperid-1-yl),        —SO₂-(azepan-1-yl), —SO₂NHMe, —SO₂NMe₂, —SO₂NHEt, —SO₂NH(i-Pr),        or —SO₂NH-cyclopropyl. In other embodiments, the present        invention includes compounds of Formula (II) wherein: R^(10a) is        —SO₂Et, —SO₂Pr, or —SO₂(i-Pr).

In some embodiments, the present invention includes compounds of Formula(II) wherein: R^(10b) is H, OH, NHR^(c), —NHCOR^(a), —NHCO₂R^(a),—NHCONR^(c)R^(d), —SO₂NHR^(c), —OSO₂NHR^(c), —NHSO₂NR^(c)R^(d), or—NHSO₂R^(e). In other embodiments, the present invention includescompounds of Formula (II) wherein: R^(10b) is H, OH, NH₂, —NHCO(C₁₋₄alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂NH₂, —SO₂NH₂, —NHCONR^(c)R^(d), or—OSO₂NH₂. In other embodiments, the present invention includes compoundsof Formula (II) wherein: R^(10b) is H, OH, NH₂, —NHCOMe, —NHCO₂Me,—NHCO₂Et, —NHCO₂(i-Pr), —NHSO₂NH₂, or —SO₂NH₂. In other embodiments, thepresent invention includes compounds of Formula (II) wherein: R^(10b) isH, OH, NH₂, —NHCOMe, —NHCO₂Me, —NHSO₂NH₂, or —SO₂NH₂. In otherembodiments, the present invention includes compounds of Formula (II)wherein: R^(10b) is —NHCOMe or —NHCO₂Me.

In some embodiments, the present invention includes compounds of Formula(II) wherein: R^(10c) is H, F, Cl, or Me. In other embodiments, thepresent invention includes compounds of Formula (II) wherein: R^(10c) isH.

In a seventh embodiment, the present invention includes the compounds ofFormula (III):

or a stereoisomer or pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein:

W is

X¹ is CH or N;

R¹ is Cl, Br, Me, Et, OMe, OEt, OCHF₂, or cyclopropyl;

R² is H, F, Cl, OMe, O(i-Pr), or OCHF₂;

R³ is H or OMe;

R⁴ is H, F, Cl, or OMe;

R⁷ is H, Me, —CH₂CO₂H, or —CH₂CO₂(C₁₋₄ alkyl);

R⁸ is H, Me, CO₂H, CO₂(C₁₋₄ alkyl), —CH₂CO₂H, or —CH₂CO₂(C₁₋₄ alkyl);

R^(10a) is H, F, O(C₁₋₄ alkyl), CONR^(c)R^(d), —S(C₁₋₄ alkyl), —SO₂(C₁₋₄alkyl), —SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl,—SO₂-(pyrrolidin-1-yl), —SO₂— (piperid-1-yl), —SO₂-(azepan-1-yl),—SO₂NR^(c)R^(d), —SO₂NH-cyclopropyl, morpholin-4-yl,3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl;

R^(10b) is H, OH, NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂NH₂,—SO₂NH₂, or —NHCONR^(c)R^(d);

R^(10c) is H, Cl, or Me;

R^(c) and R^(d) are, independently at each occurrence, H or C₁₋₄ alkyl;

alternatively, R^(c) and R^(d), when attached to the same nitrogen atom,combine to form a 4- to 5-membered heterocycle comprising: carbon atomsand 0-2 additional heteroatoms selected from N, O, and S(O)_(p); whereinsaid heterocycle is substituted with 0-2 R^(g); and

R^(g) is, independently at each occurrence, ═O, F, Cl, Br, CF₃, OH, orC₁₋₄ alkyl;

provided that when R⁸ is H, X¹ is CH, and R^(10a) and R^(10c) are H,then R^(10b) is other than H; additionally, provided that any two of R²,R⁸, R^(10a), and R^(10b) are other than H.

In an eighth embodiment, the present invention includes the compounds ofFormula (III), within the scope of the seventh embodiment wherein:

W is

X¹ is CH;

R⁷ is H, Me, or —CH₂CO₂H;

R⁸ is H, Me, CO₂H, —CH₂CO₂H, or —CH₂CO₂Me;

R^(10a) is H, F, O(i-Pr), —CONMe₂, —CO-(pyrrolidin-1-yl),—CO-(piperid-1-yl), —S(i-Pr), —SO₂Et, —SO₂Pr, —SO₂(i-Pr), —SO₂(t-Bu),—SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl, —SO₂—(pyrrolidin-1-yl), —SO₂— (piperid-1-yl), —SO₂-(azepan-1-yl), —SO₂NHMe,—SO₂NMe₂, —SO₂NHEt, —SO₂NH(i-Pr), —SO₂NH-cyclopropyl, morpholin-4-yl,3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl;

R^(10b) is H, OH, NH₂, —NHCOMe, —NHCOPr, —NHCO₂Me, —NHCO₂Et,—NHCO₂(i-Pr), —NHCO₂(i-Bu), —NHSO₂NH₂, —SO₂NH₂, —NHCON(Me)₂,—NHCON(Me)(Et), —NHCON(Me)(i-Pr),

R^(10c) is H;

provided that when R⁸ is H, X¹ is CH, and R^(10a) and R^(10c) are H,then R^(10b) is other than H; additionally, provided that any two of R²,R⁸, R^(10a), and R^(10b) are other than H.

In some embodiments, the present invention includes compounds of Formula(III) wherein: W is

In other embodiments, the present invention includes compounds ofFormula (III) wherein: W is

In some embodiments, the present invention includes compounds of Formula(III) wherein: X¹ is CH.

In some embodiments, the present invention includes compounds of Formula(III) wherein: R¹ is OMe or OEt. In other embodiments, the presentinvention includes compounds of Formula (III) wherein: R¹ is OMe. Inother embodiments, the present invention includes compounds of Formula(III) wherein: R¹ is OEt.

In some embodiments, the present invention includes compounds of Formula(III) wherein: R² is H, OMe, or O(i-Pr). In other embodiments, thepresent invention includes compounds of Formula (III) wherein: R² isOMe, or O(i-Pr). In other embodiments, the present invention includescompounds of Formula (III) wherein: R² is O(i-Pr).

In some embodiments, the present invention includes compounds of Formula(III) wherein: R⁴ is H.

In some embodiments, the present invention includes compounds of Formula(III) wherein: R⁷ is H or Me. In other embodiments, the presentinvention includes compounds of Formula (III) wherein: R⁷ is H.

In some embodiments, the present invention includes compounds of Formula(III) wherein: R⁸ is H or Me. In other embodiments, the presentinvention includes compounds of Formula (III) wherein: R⁸ is H.

In some embodiments, the present invention includes compounds of Formula(III) wherein: R^(10a) is CONMe₂, —CO-(pyrrolidin-1-yl),—CO-(piperid-1-yl), —S(i-Pr), —SO₂Et, —SO₂Pr, —SO₂(i-Pr), —SO₂(t-Bu),—SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl,—SO₂-(pyrrolidin-1-yl), —SO₂— (piperid-1-yl), —SO₂-(azepan-1-yl),—SO₂NHMe, —SO₂NMe₂, —SO₂NHEt, —SO₂NH(i-Pr), or —SO₂NH-cyclopropyl. Inother embodiments, the present invention includes compounds of Formula(III) wherein: R^(10a) is —SO₂Et, —SO₂Pr, —SO₂(i-Pr), —SO₂(t-Bu),—SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl, —SO₂—(pyrrolidin-1-yl), —SO₂— (piperid-1-yl), —SO₂-(azepan-1-yl), —SO₂NHMe,—SO₂NMe₂, —SO₂NHEt, —SO₂NH(i-Pr), or —SO₂NH-cyclopropyl. In otherembodiments, the present invention includes compounds of Formula (III)wherein: R^(10a) is —SO₂Et, —SO₂Pr, or —SO₂(i-Pr).

In some embodiments, the present invention includes compounds of Formula(III) wherein: R^(10b) is H, —NHCOMe, —NHCO₂Me, —NHSO₂NH₂, or —SO₂NH₂.In other embodiments, the present invention includes compounds ofFormula (III) wherein: R^(10b) is —NHCOMe or —NHCO₂Me.

In some embodiments, the present invention includes compounds of Formula(III) wherein: R^(10c) is H.

In a ninth embodiment, the present invention provides, inter alia,compounds of Formula (IV):

or a stereoisomer or pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein:

W₁ is substituted with 0-2 R⁶ and selected from:

X is CH, CR⁶, or N;

Y is selected from:

R¹ is independently at each occurrence, H, F, Cl, Br, I, C₁₋₄ alkylsubstituted with 0-1OH, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ haloalkyl, —O—C₁₋₄ haloalkyl, or C₃₋₆ cycloalkyl;

R² and R³ are, independently at each occurrence, selected from: H, F,Cl, Br, I, OR^(a), SR^(e), OCF₃, OCHF₂, OCH₂F, CN, NO₂, —NR^(c)R^(d),—C(O)R^(a), —CO₂R^(a), —NR^(c)C(O)R^(a), —C(O)NR^(c)R^(d),—NR^(c)C(O)OR^(e), —NR^(c)C(O)NR^(c)R^(d), —OC(O)NR^(c)R^(d),—SO₂NR^(c)R^(d), —NR^(c)SO₂NR^(c)R^(d), —NR^(c)SO₂R^(e), —NR^(c)SO₂CF₃,—SO₂CF₃, —S(O)₂R^(e), C₁₋₄ alkyl substituted with 0-2 R^(f), C₂₋₄alkenyl substituted with 0-2 R^(f), and C₂₋₄ alkynyl substituted with0-2 R^(f);

R⁴ is, independently at each occurrence, H, F, Cl, Br, I, OR^(a),SR^(e), OCF₃, OCHF₂, OCH₂F, CN, NO₂, —NR^(c)R^(d), —C(O)R^(a),—CO₂R^(a), —NR^(c)C(O)R^(a), —C(O)NR^(c)R^(d), —NR^(c)C(O)OR^(e),—NR^(c)C(O)NR^(c)R^(d), —OC(O)NR^(c)R^(d), —SO₂NR^(c)R^(d),—NR^(c)SO₂NR^(c)R^(d), —NR^(c)SO₂R^(e), —NR^(c)SO₂CF₃, —SO₂CF₃,—S(O)₂R^(e), —OCH₂CO₂R^(a), —O(benzyl substituted with CO₂R^(a)),tetrazolyl, —SO₂NHCOR^(a), —CONHSO₂R^(e), C₁₋₄ alkyl substituted with0-2 R^(f), C₂₋₄ alkenyl substituted with 0-2 R^(f), or C₂₋₄ alkynylsubstituted with 0-2 R^(f);

alternatively, R² and R³ may combine to form a 5- to 7-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-4 heteroatomsselected from N, NR^(c), O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 0-3 R^(f);

alternatively, R³ and R⁴ may combine to form a 5- to 7-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-4 heteroatomsselected from N, NR^(c), O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 0-3 R^(f);

R⁶ is, independently at each occurrence, F, Cl, Br, C₁₋₃ alkyl, or C₁₋₃alkoxy;

R⁷ is H, C₁₋₄ alkyl, —CH₂CO₂R^(a), —CH₂CH₂CO₂R^(a), —CH₂CH₂OH,—CH₂CH₂CH₂OH, tetrazolyl, —CH₂CONHSO₂R^(e), or —CH₂CH₂CONHSO₂R^(e);

R⁸ is H, C₁₋₄ alkyl, CO₂R^(a), —CH₂CO₂R^(a), —CH₂OH, —CH₂CH₂OH,tetrazolyl, —CONHSO₂R^(e), or —CH₂CONHSO₂R^(e);

R⁹ is H or C₁₋₄ alkyl;

alternatively, R⁸ and R⁹ can be taken together with the carbon atom towhich they are attached to form a 3- to 5-membered carbocycle;

Z is phenyl substituted with 0-3 R¹⁰ or pyridyl substituted with 0-3R¹⁰;

R¹⁰ is, independently at each occurrence, F, Cl, Br, CN, CH₂F, CHF₂,CF₃, OCF₃, SCF₃, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, —(CH₂)_(n)—OR^(a),SR^(e), —(CH₂)_(n)—NR^(c)R^(d), CO₂R^(a), CONR^(c)R^(d), —SO₂R^(e),—SO₂NR^(c)R^(d), —NR^(h)COR^(a), —NR^(h)CO₂R^(a), —NR^(h)CONR^(c)R^(d),—OC(O)NR^(c)R^(d), —SO₂NR^(c)R^(d), —OSO₂NR^(c)R^(d),—NR^(h)SO₂NR^(c)R^(d), —NR^(h)SO₂R^(e), —B(OH)₂, —(CH₂)_(n)-phenyl,—NH-phenyl, —NH(-5- to 6-membered heteroaryl comprising: carbon atomsand 1-3 heteroatoms selected from N, O, and S(O)_(p)), or —(CH₂)_(n)-5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said phenyl, heteroaryl andheterocycle are substituted with 0-3 R^(i);

alternatively, when two R¹⁰ groups are substituted on adjacent ringatoms, they can be taken together with the ring atoms to which they areattached to form a 5- to 7-membered carbocycle or heterocyclecomprising: carbon atoms and 0-4 heteroatoms selected from N, O, andS(O)_(p), wherein said carbocycle or heterocycle is substituted with 0-2R^(i);

R¹¹ is H or C₁₋₃ alkyl;

R^(a) is, independently at each occurrence, H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, phenyl, or benzyl; wherein said alkyl, cycloalkyl, phenyland benzyl are optionally substituted with 0-2 R^(f);

R^(c) and R^(d) are, independently at each occurrence, H, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, phenyl, or benzyl;

alternatively, R^(c) and R^(d), when attached to the same nitrogen atom,combine to form a 3- to 7-membered heterocycle comprising: carbon atomsand 0-2 additional heteroatoms selected from N, O, and S(O)_(p); whereinsaid heterocycle is substituted with 0-2 R^(g);

R^(e) is, independently at each occurrence, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,phenyl, or benzyl;

R^(f) is, independently at each occurrence, F, CF₃, OH, C₁₋₃ alkoxy, orC₃₋₆ cycloalkyl;

R^(g) is, independently at each occurrence, ═O, F, Cl, Br, CF₃, OH, orC₁₋₄ alkyl;

R^(h) is, independently at each occurrence, H or C₁₋₃ alkyl;

R^(i) is, independently at each occurrence, F, Cl, Br, CF₃, OH, or C₁₋₄alkyl; n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and p,at each occurrence, is selected from 0, 1, and 2;

provided that when R⁸ and R⁹ are both H, then Z is other thanunsubstituted phenyl.

In a tenth embodiment, the present invention includes the compounds ofFormula (IV), within the scope of the ninth embodiment wherein:

R¹ is F, Cl, Br, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio,C₃₋₆ cycloalkyl, OCF₃, OCHF₂, or OCH₂F;

R² and R³ are, independently at each occurrence, selected from: H, F,Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, OCHF₂, or OCH₂F;

R⁴ is, independently at each occurrence, H, F, Cl, Br, C₁₋₄ alkyl, orC₁₋₄ alkoxy;

R⁶ is, independently at each occurrence, F, Cl, Me or OMe;

R⁷ is H, C₁₋₄ alkyl, or —CH₂CO₂R^(a); and

R⁸ is H, C₁₋₄ alkyl, CO₂R^(a), or —CH₂CO₂R^(a);

provided that when R⁸ and R⁹ are both H, then Z is other thanunsubstituted phenyl.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: W₁ is

substituted with 0-2 R⁶.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: X is CH.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: Y is:

In some embodiments, the present invention includes compounds of Formula(IV) wherein: Y is selected from:

In some embodiments, the present invention includes compounds of Formula(IV) wherein: F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCHF₂, or cyclopropyl.In other embodiments, the present invention includes compounds ofFormula (IV) wherein: R¹ is F, Cl, Br, Me, Et, Pr, i-Pr, vinyl,2-propenyl, allyl, OMe, OEt, OPr, OCHF₂, SMe, SEt, or cyclopropyl. Inother embodiments, the present invention includes compounds of Formula(IV) wherein: R¹ is Cl, Br, Me, Et, Pr, i-Pr, vinyl, 2-propenyl, OMe,OEt, OPr, OCHF₂, or cyclopropyl. In other embodiments, the presentinvention includes compounds of Formula (IV) wherein: R¹ is Cl, Br, Me,Et, OMe, OEt, OPr, OCHF₂, or cyclopropyl. In other embodiments, thepresent invention includes compounds of Formula (IV) wherein: R¹ is OMeor OEt.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: R² is H, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, or OCHF₂. Inother embodiments, the present invention includes compounds of Formula(IV) wherein: R² is H, F, Cl, Br, C₁₋₄ alkoxy, or OCHF₂. In otherembodiments, the present invention includes compounds of Formula (IV)wherein: R² is H, F, Cl, OMe, O(i-Pr), or OCHF₂. In other embodiments,the present invention includes compounds of Formula (IV) wherein: R² isH, OMe, or O(i-Pr).

In some embodiments, the present invention includes compounds of Formula(IV) wherein: R³ is H, F, Cl, Br, C₁₋₄ alkyl, C₁₋₄ alkoxy, or OCHF₂. Inother embodiments, the present invention includes compounds of Formula(IV) wherein: R³ is H or C₁₋₄ alkoxy. In other embodiments, the presentinvention includes compounds of Formula (IV) wherein: R³ is H.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: R⁴ is H, F, Cl, Br, C₁₋₄ alkyl, or C₁₋₄ alkoxy. In otherembodiments, the present invention includes compounds of Formula (IV)wherein: R⁴ is H, F, Cl, or C₁₋₃ alkoxy. In other embodiments, thepresent invention includes compounds of Formula (IV) wherein: R⁴ is H,F, Cl, or OMe.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: R⁶ is, independently at each occurrence, F, Cl, Me or OMe.In other embodiments, the present invention includes compounds ofFormula (IV) wherein: R⁶ is, independently at each occurrence, F, Cl, orMe.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: R⁷ is H, Me, —CH₂CO₂H, —CH₂CO₂Me, or —CH₂CO₂Et. In otherembodiments, the present invention includes compounds of Formula (IV)wherein: R⁷ is H or Me.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: R⁸ is H, Me, CO₂H, CO₂Me, CO₂Et, —CH₂CO₂H, —CH₂CO₂Me, or—CH₂CO₂Et. In other embodiments, the present invention includescompounds of Formula (IV) wherein: R⁸ is H or Me.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: R⁹ is H.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: R¹⁰ is, independently at each occurrence, F, Cl, Br, CF₃,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, OR^(a), SR^(e), NR^(c)R^(d),—CH₂NR^(c)R^(d), CONR^(c)R^(d), —SO₂R^(e), —SO₂NR^(c)R^(d), —NHCOR^(a),—NHCO₂R^(a), —NHCONR^(c)R^(d), —OSO₂NR^(c)R^(d), —NHSO₂NR^(c)R^(d),—NHSO₂R^(e), —B(OH)₂, phenyl substituted with 0-2 R^(i), or a 5- to6-membered heterocycle substituted with 0-2 R^(i) and selected from:morpholinyl, piperidyl, pyrazolyl, and triazolyl. In other embodiments,the present invention includes compounds of Formula (IV) wherein: R¹⁰is, independently at each occurrence, F, Cl, Br, C₁₋₄ alkyl, C₂₋₄alkenyl, OR^(a), SR^(e), NR^(c)R^(d), —CH₂NR^(c)R^(d), CONR^(c)R^(d),—SO₂R^(e), —SO₂NR^(c)R^(d), —NHCOR^(a), —NHCO₂R^(a), —NHCONR^(c)R^(d),—OSO₂NR^(c)R^(d), —NHSO₂NR^(c)R^(d), —NHSO₂R^(e), morpholin-4-yl,piperid-1-yl, 3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl. Inother embodiments, the present invention includes compounds of Formula(IV) wherein: R¹⁰ is, independently at each occurrence, CONR^(c)R^(d),—SO₂R^(e), —SO₂NR^(c)R^(d), —NHCOR^(a), —NHCO₂R^(a), —NHCONR^(c)R^(d),—OSO₂NR^(c)R^(d), —NHSO₂NR^(c)R^(d), or —NHSO₂R^(e).

In some embodiments, the present invention includes compounds of Formula(IV) wherein: R¹¹ is H.

In some embodiments, the present invention includes compounds of Formula(IV) wherein: Z is phenyl substituted with 0-3 R¹⁰.

In an eleventh embodiment, the present invention includes the compoundsof Formula (V):

or a stereoisomer or pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein:

W₁ is substituted with 0-2 R⁶ and selected from:

X is CH or N;

X¹ is CH or N;

X² is CH or N;

X³ is CR^(10c) or N;

provided that only one of X¹, X² and X³ may be N;

R¹ is H, F, Cl, Br, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₃₋₆ cycloalkyl, OCF₃, OCHF₂, or OCH₂F;

R² and R³ are independently selected from: H, F, Cl, Br, I, OR^(a),SR^(e), OCF₃, OCHF₂, OCH₂F, CN, NO₂, —NR^(c)R^(d), —C(O)R^(a),—CO₂R^(a), —NR^(c)C(O)R^(a), —C(O)NR^(c)R^(d), —NR^(c)C(O)OR^(e),—NR^(c)C(O)NR^(c)R^(d), —OC(O)NR^(c)R^(d), —SO₂NR^(c)R^(d),—NR^(c)SO₂NR^(c)R^(d), —NR^(c)SO₂R^(e), —NR^(c)SO₂CF₃, —SO₂CF₃,—S(O)₂R^(e), C₁₋₄ alkyl substituted with 0-2 R^(f), C₂₋₄ alkenylsubstituted with 0-2 R^(f), and C₂₋₄ alkynyl substituted with 0-2 R^(f);

R⁴ is H, F, Cl, Br, I, OR^(a), SR^(e), OCF₃, CN, NO₂, —NR^(c)R^(d),—C(O)R^(a), —CO₂R^(a), —NR^(c)C(O)R^(a), —C(O)NR^(c)R^(d),—NR^(c)C(O)OR^(e), —NR^(c)C(O)NR^(c)R^(d), —OC(O)NR^(c)R^(d),—SO₂NR^(c)R^(d), —NR^(c)SO₂NR^(c)R^(d), —NR^(c)SO₂R^(e), —NR^(c)SO₂CF₃,—SO₂CF₃, —S(O)₂R^(e), —OCH₂CO₂R^(a), —O(benzyl substituted withCO₂R^(a)), tetrazolyl, SO₂NHCOR^(a), —CONHSO₂R^(e), C₁₋₄ alkylsubstituted with 0-2 R^(f), C₂₋₄ alkenyl substituted with 0-2 R^(f),C₂₋₄ alkynyl substituted with 0-2 R^(f);

alternatively, R² and R³ may combine to form a 5- to 6-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-3 heteroatomsselected from N, NR^(c), O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 0-3 R^(f);

R⁶ is, independently at each occurrence, F, Cl, Br, C₁₋₃ alkoxy or C₁₋₃alkyl;

R⁷ is H, C₁₋₄ alkyl, —CH₂CO₂R^(a), —CH₂CH₂CO₂R^(a), —CH₂CH₂OH,—CH₂CH₂CH₂OH, tetrazolyl, —CH₂CONHSO₂R^(e), or —CH₂CH₂CONHSO₂R^(e);

R⁸ is H, C₁₋₄ alkyl, CO₂R^(a), —CH₂CO₂R^(a), —CH₂OH, —CH₂CH₂OH,tetrazolyl, CONHSO₂R^(e), or —CH₂CONHSO₂R^(e);

R⁹ is H or Me;

alternatively, R⁸ and R⁹ can be taken together with the carbon atom towhich they are attached to form a 3- to 5-membered carbocycle;

R^(10a) is H, F, Cl, Br, CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, OR^(a), SR^(e),NR^(c)R^(d), CONR^(c)R^(d), —SO₂R^(e), —SO₂NR^(c)R^(d), phenylsubstituted with 0-2 R^(i), or a 5- to 6-membered heterocyclesubstituted with 0-2 R^(i) and selected from: morpholinyl, piperidyl,pyrazolyl, and triazolyl;

R^(10b) is H, OR^(a), NR^(c)R^(d), —NHCOR^(a), —NHCO₂R^(a),—NHCONR^(c)R^(d), —SO₂NR^(c)R^(d), —OSO₂NR^(c)R^(d), —NHSO₂NR^(c)R^(d),—NHSO₂R^(e), —B(OH)₂, —NH(-5 to 6-membered heteroaryl comprising: carbonatoms and 1-3 heteroatoms selected from N, O, and S(O)_(p) andsubstituted with 0-2 R^(i)), —NH-phenyl substituted with 0-2 R^(i), or a5-membered heterocycle substituted with 0-2 R^(i) and selected from:tetrazolyl, pyrazolyl, pyrrolyl, and triazolyl;

R^(10c) is H, F, Cl, Br, CF₃, C₁₋₆ alkyl, OR^(a), SR^(e), orNR^(c)R^(d);

R¹¹ is H;

R^(a) is, independently at each occurrence, H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, phenyl, or benzyl; wherein said alkyl, cycloalkyl, phenyland benzyl are optionally substituted with 0-2 R^(f);

R^(c) and R^(d) are, independently at each occurrence, H, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, phenyl, or benzyl;

alternatively, R^(c) and R^(d), when attached to the same nitrogen atom,combine to form a 4- to 7-membered heterocycle comprising: carbon atomsand 0-2 additional heteroatoms selected from N, O, and S(O)_(p); whereinsaid heterocycle is substituted with 0-2 R^(g);

R^(e) is, independently at each occurrence, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,phenyl, or benzyl;

R^(f) is, independently at each occurrence, F, CF₃, OH, C₁₋₃ alkoxy, orC₃₋₆ cycloalkyl;

R^(g) is, independently at each occurrence, ═O, F, Cl, Br, CF₃, OH, orC₁₋₄ alkyl;

R^(i) is, independently at each occurrence, F, Cl, Br, CF₃, OH, or C₁₋₄alkyl; n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and p,at each occurrence, is selected from 0, 1, and 2;

provided that when R⁸ and R⁹ are both H, X¹, X², and X³ are CH, andR^(10a) is H, then R^(10b) is other than H.

In a twelfth embodiment, the present invention includes the compounds ofFormula (V), within the scope of the eleventh embodiment wherein:

W₁ is

R¹ is F, Cl, Br, Me, Et, Pr, i-Pr, vinyl, 2-propenyl, allyl, OMe, OEt,OPr, OCHF₂, SMe, SEt, or cyclopropyl;

R² and R³ are independently selected from: H, F, Cl, Br, C₁₋₄ alkyl,C₁₋₄ alkoxy, or OCHF₂;

alternatively, R² and R³ may combine to form a 5- to 6-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-3 heteroatomsselected from N, NR^(c), O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 0-3 R^(f);

R⁴ is H, F, Cl, Br, C₁₋₄ alkyl, or C₁₋₄ alkoxy;

R⁶ is, independently at each occurrence, F, Cl, C₁₋₃ alkoxy or C₁₋₃alkyl;

R⁷ is H, C₁₋₄ alkyl, or —CH₂CO₂R^(a);

R⁸ is H, C₁₋₄ alkyl, CO₂R^(a), or —CH₂CO₂R^(a);

R^(10a) is H, F, Cl, Br, C₁₋₄ alkyl, C₂₋₄ alkenyl, OR^(a), SR^(e),CONR^(c)R^(d), —SO₂R^(e), —SO₂NR^(c)R^(d), morpholin-4-yl, piperid-1-yl,3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl;

R^(10b) is H, OH, NHR^(c), —NHCOR^(a), —NHCO₂R^(a), —NHCONR^(c)R^(d),—SO₂NHR^(c), —OSO₂NHR^(c), —NHSO₂NR^(c)R^(d), or —NHSO₂R^(e); and

R^(10c) is H, F, Cl, Br, C₁₋₄ alkyl, or NR^(c)R^(d);

provided that when R⁸ is H, X¹, X², and X³ are CH, and R^(10a) is H,then R^(10b) is other than H.

In a thirteenth embodiment, the present invention includes the compoundsof Formula (V), within the scope of the twelfth embodiment wherein:

R¹ is Cl, Br, Me, Et, OMe, OEt, OCHF₂, or cyclopropyl;

R² is H, F, Cl, OMe, O(i-Pr), or OCHF₂;

R³ is H or OMe;

alternatively, R² and R³ may combine to form a 5-membered heterocyclecomprising: carbon atoms and 1-3 heteroatoms selected from N, NR^(c), O,and S(O)_(p), wherein said heterocycle is substituted with 0-3 R^(f);

R⁴ is H, F, Cl, or OMe;

R⁶ is, independently at each occurrence, F, Cl, or Me;

R⁷ is H, Me, —CH₂CO₂H, or —CH₂CO₂(C₁₋₄ alkyl);

R⁸ is H, Me, CO₂H, CO₂(C₁₋₄ alkyl), —CH₂CO₂H, or —CH₂CO₂(C₁₋₄ alkyl);

R⁹ is H;

R^(10a) is H, F, O(C₁₋₄ alkyl), CONR^(c)R^(d), —S(C₁₋₄ alkyl), —SO₂(C₁₋₄alkyl), —SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl,—SO₂-(pyrrolidin-1-yl), —SO₂— (piperid-1-yl), —SO₂-(azepan-1-yl),—SO₂NR^(c)R^(d), —SO₂NH-cyclopropyl, morpholin-4-yl,3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl;

R^(10b) is H, OH, NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂NH₂,—SO₂NH₂, or —NHCONR^(c)R^(d);

R^(10c) is H, F, Cl, or Me; R^(c) and R^(d) are, independently at eachoccurrence, H or C₁₋₄ alkyl;

alternatively, R^(c) and R^(d), when attached to the same nitrogen atom,combine to form a 4- to 5-membered heterocycle comprising: carbon atomsand 0-2 additional heteroatoms selected from N, O, and S(O)_(p); whereinsaid heterocycle is substituted with 0-2 R^(g); and

R^(g) is, independently at each occurrence, ═O, F, Cl, Br, CF₃, OH, orC₁₋₄ alkyl;

provided that when R⁸ is H, X¹, X², and X³ are CH, and R^(10a) is H,then R^(10b) is other than H; additionally, provided that any two of R²,R⁸, R^(10a), and R^(10b) are other than H.

In a fourteenth embodiment, the present invention includes the compoundsof Formula (V), within the scope of the thirteenth embodiment wherein:

W₁ is:

X¹ is CH;

R⁷ is H, Me, or —CH₂CO₂H;

R⁸ is H, Me, CO₂H, —CH₂CO₂H, or —CH₂CO₂Me;

R^(10a) is H, F, O(i-Pr), CONMe₂, —CO-(pyrrolidin-1-yl),—CO-(piperid-1-yl), —S(i-Pr), —SO₂Et, —SO₂Pr, —SO₂(i-Pr), —SO₂(t-Bu),—SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl,—SO₂-(pyrrolidin-1-yl), —SO₂— (piperid-1-yl), —SO₂-(azepan-1-yl),—SO₂NHMe, —SO₂NMe₂, —SO₂NHEt, —SO₂NH(i-Pr), —SO₂NH-cyclopropyl,morpholin-4-yl, 3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl;

R^(10b) is H, OH, NH₂, —NHCOMe, —NHCOPr, —NHCO₂Me, —NHCO₂Et,—NHCO₂(i-Pr), —NHCO₂(i-Bu), —NHSO₂NH₂, —SO₂NH₂, —NHCON(Me)₂,—NHCON(Me)(Et), —NHCON(Me)(i-Pr),

R^(10c) is H;

provided that when R⁸ is H, R^(10a) is H, then R^(10b) is other than H;additionally, provided that any two of R², R⁸, R^(10a), and R^(10b) areother than H.

In a fifteenth embodiment, the present invention includes the compoundsof Formula (V), within the scope of the fourteenth embodiment wherein:

R¹ is OEt;

R² is, H, F, Cl, OMe, or O(i-Pr);

R⁴ is H or F;

R⁷ is H or Me;

R⁸ is H or Me;

R^(10a) is —SO₂Et;

R^(10b) is —NHCOMe.

In a sixteenth aspect, the present invention provides a compoundselected from the exemplified compounds or a stereoisomer orpharmaceutically acceptable salt, solvate, or prodrug thereof.

In a seventeenth embodiment, the present invention includes a compoundof Formula (IIa):

wherein: W, R¹, R², R³, R⁴, R⁷, R⁸, R⁹, R^(10a), R^(10b), X¹, X², and X³are the same as defined in the third embodiment.

In an eighteen embodiment, the present invention includes a compound ofFormula (Va):

wherein: W₁, R¹, R², R³, R⁴, R⁷, R⁸, R⁹, R^(10a), R^(10b), X¹, X², andX³ are the same as defined in the eleventh embodiment.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, tautomer, pharmaceuticallyacceptable salt, solvate, or prodrug thereof.

In another embodiment, the present invention provides a novel processfor making one of the compounds of the present invention or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof.

In another embodiment, the present invention provides a novelintermediate for making one of the compounds of the present invention ora stereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof.

In another embodiment the present invention provides a method formodulation of the coagulation cascade and/or contact activation systemcomprising administering to a patient in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, tautomer, pharmaceuticallyacceptable salt, solvate, or prodrug thereof.

In another embodiment the present invention provides a method fortreating thrombotic or thromboembolic disorders comprising:administering to a patient in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a stereoisomer, tautomer, pharmaceutically acceptable salt,solvate, or prodrug thereof.

In another embodiment, the thromboembolic disorder is selected from thegroup consisting of arterial cardiovascular thromboembolic disorders,venous cardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.

In another embodiment, the thromboembolic disorder is selected fromunstable angina, an acute coronary syndrome, atrial fibrillation, firstmyocardial infarction, recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, peripheralocclusive arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis.

In another embodiment, the present invention provides a method fortreating inflammatory disorders comprising: administering to a patientin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, the present invention provides a method, whereinthe inflammatory disorder is selected from the group consisting ofsepsis, acute respiratory dystress syndrome, and systemic inflammatoryresponse syndrome.

In another embodiment, the present invention provides a novel method oftreating a patient in need of thromboembolic disorder treatment,comprising: administering a compound of the present invention or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate, orprodrug thereof in an amount effective to treat a thromboembolicdisorder.

In another embodiment, the present invention provides a method oftreating a patient in need of inflammatory disorder treatment,comprising: administering a compound of the present invention or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate, orprodrug thereof in an amount effective to treat an inflammatorydisorder.

In another embodiment, the present invention provides a method,comprising: administering a compound of the present invention or astereoisomer, tautomer, pharmaceutically acceptable salt form thereof inan amount effective to treat a thrombotic or thromboembolic and/orinflammatory disorder.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising at least one additional therapeutic agentselected from one or more of potassium channel openers, potassiumchannel blockers, calcium channel blockers, sodium hydrogen exchangerinhibitors, antiarrhythmic agents, antiatherosclerotic agents,anticoagulants, antithrombotic agents, prothrombolytic agents,fibrinogen antagonists, diuretics, antihypertensive agents, ATPaseinhibitors, mineralocorticoid receptor antagonists, phosphodiesteraseinhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants,angiogenesis modulators, antiosteoporosis agents, hormone replacementtherapies, hormone receptor modulators, oral contraceptives, antiobesityagents, antidepressants, antianxiety agents, antipsychotic agents,antiproliferative agents, antitumor agents, antiulcer andgastroesophageal reflux disease agents, growth hormone agents and/orgrowth hormone secretagogues, thyroid mimetics, anti-infective agents,antiviral agents, antibacterial agents, antifungal agents,cholesterol/lipid lowering agents and lipid profile therapies, andagents that mimic ischemic preconditioning and/or myocardial stunning,or a combination thereof.

In a preferred embodiment, the present invention provides apharmaceutical composition wherein the additional therapeutic agent(s)is an antihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, beta-adrenergic receptor antagonists, ETA receptorantagonists, dual ETA/AT-1 receptor antagonists, and vasopeptidaseinhibitors, an antiarrythmic agent selected from IKur inhibitors, ananticoagulant agent selected from thrombin inhibitors, antithrombin-IIIactivators, heparin co-factor II activators, other factor VIIainhibitors, other plasma kallikrein inhibitors, plasminogen activatorinhibitor (PAI-1) antagonists, thrombin activatable fibrinolysisinhibitor (TAFI) inhibitors, factor IXa inhibitors, factor Xainhibitors, and factor XIa inhibitors, or an antiplatelet agent selectedfrom GPIIb/IIIa blockers, protease activated receptor (PAR-1)antagonists, phosphodiesterase-III inhibitors, P2Y₁ receptorantagonists, P2Y₁₂ receptor antagonists, thromboxane receptorantagonists, cyclooxygense-1 inhibitors, and aspirin, or a combinationthereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom an anti-arrhythmic agent, an anti-hypertensive agent, ananti-coagulant agent, an anti-platelet agent, a thrombin inhibitingagent, a thrombolytic agent, a fibrinolytic agent, a calcium channelblocker, a potassium channel blocker, a cholesterol/lipid loweringagent, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In a preferred embodiment, the present invention provides apharmaceutical composition, wherein the additional therapeutic agent(s)are an anti-platelet agent or a combination thereof.

In a preferred embodiment, the present invention provides apharmaceutical composition, wherein the additional therapeutic agent isthe anti-platelet agent selected from clopidogrel and aspirin, or acombination thereof.

In a preferred embodiment, the present invention provides apharmaceutical composition, wherein the additional therapeutic agent isthe anti-platelet agent clopidogrel.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for treating a thrombotic andthromboembolic disorder.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment of a thrombotic or thromboembolic disorder.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intreatment of a thrombotic or thromboembolic disorder.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention; and (c) a package insert stating that thepharmaceutical composition can be used for the treatment of a thromboticor thromboembolic disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising: (d) a second container;wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention; and (c) a package insert stating that thepharmaceutical composition can be used in combination with a secondtherapeutic agent to treat a thrombotic or thromboembolic disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising: (d) a second container;wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional more preferredembodiments. It is also to be understood that each individual element ofthe preferred embodiments is its own independent preferred embodiment.Furthermore, any element of an embodiment is meant to be combined withany and all other elements from any embodiment to describe an additionalembodiment.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis using optically active starting materialsor optically active catalysts. Geometric isomers of double bonds such asolefins and C═N double bonds can also be present in the compoundsdescribed herein, and all such stable isomers are contemplated in thepresent invention. Cis and trans geometric isomers of the compounds ofthe present invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. When no specific mention is made of theconfiguration (cis, trans or R or S) of a compound (or of an asymmetriccarbon), then any one of the isomers or a mixture of more than oneisomer is intended. The processes for preparation can use racemates,enantiomers, or diastereomers as starting materials. All processes usedto prepare compounds of the present invention and intermediates madetherein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they can beseparated by conventional methods, for example, by chromatography orfractional crystallization. Compounds of the present invention, andsalts thereof, may exist in multiple tautomeric forms, in which hydrogenatoms are transposed to other parts of the molecules and the chemicalbonds between the atoms of the molecules are consequently rearranged. Itshould be understood that all tautomeric forms, insofar as they mayexist, are included within the invention. The inventive compounds may bein the free or hydrate form.

Preferably, the molecular weight of compounds of the present inventionis less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole.Preferably, the molecular weight is less than about 800 grams per mole.More preferably, the molecular weight is less than about 750 grams permole. Even more preferably, the molecular weight is less than about 700grams per mole.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbon atom of the carbonyl group or one carbon atom of thedouble bond be part of (i.e., within) the ring. Ring double bonds, asused herein, are double bonds that are formed between two adjacent ringatoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these can be converted to N-oxides by treatmentwith an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, all shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative. In cases wherein there are quarternary carbonatoms on compounds of the present invention, these may be replaced bysilicon atoms, provided they do not form Si—N or Si—O bond.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R¹⁰, then said group mayoptionally be substituted with up to three R¹⁰ groups and R^(2b) at eachoccurrence is selected independently from the definition of R¹⁰. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁-C₁₀ alkyl”or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂, C₃, C₄,C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, for example,“C₁₋₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Alkyl groups canbe unsubstituted or substituted so that one or more of its hydrogens arereplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither a straight or branched configuration having the specified numberof carbon atoms and one or more unsaturated carbon-carbon bonds whichmay occur in any stable point along the chain. For example, “C₂₋₆alkenyl” (or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆alkenyl groups. Examples of alkenyl include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3,pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or morecarbon-carbon triple bonds which may occur in any stable point along thechain. For example, “C₂₋₆ alkynyl” (or alkynylene), is intended toinclude C₂, C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl,propynyl, butynyl, pentynyl, hexynyl and the like.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to includeC₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. Branched cycloalkyl groups such as1-methylcyclopropyl and 2-methylcyclopropyl are included in thedefinition of “cycloalkyl”.

“Alkoxy” or “alkyloxy” represents an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.For example, “C₁-C₆ alkoxy” (or alkyloxy), is intended to include C₁,C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Examples of alkoxy include, butare not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, “alkylthio” or“thioalkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample methyl-S—, ethyl-S—, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” which is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁-C₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly,“haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example trifluoromethyl-S—, pentafluoroethyl-S—,and the like.

As used herein, “carbocycle” is intended to mean any stable 3, 4, 5, 6,7, or 8-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or13-membered bicyclic or tricyclic, any of which may be saturated,partially unsaturated, or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,or tetrahydronaphthyl (tetralin). Preferred carbocycles, unlessotherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl, and indanyl. When the term “carbocycle” is used, itis intended to include “aryl”.

As used herein, the term “aryl”, “C₆-C₁₀ aryl” or “aromatic residue”, isintended to mean an aromatic moiety containing, if specified, thespecified number of carbon atoms; for example phenyl or naphthyl. Unlessotherwise specified, “aryl”, “C₆-C₁₀ aryl” or “aromatic residue” may beunsubstituted or substituted with 0 to 3 groups selected from H, OH,OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃,SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9 or 10-membered carbocyclic ringsystem which contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5 or 6 membered carbon ring which is saturated,partially unsaturated, or unsaturated. The bicyclic carbocyclic groupmay be attached to its pendant group at any carbon atom which results ina stable structure. The bicyclic carbocyclic group described herein maybe substituted on any carbon if the resulting compound is stable.Examples of a bicyclic carbocyclic group are, but not limited to,naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5, 6, or 7-membered monocyclic or polycyclicor 7, 8, 9, 10, 11, 12, 13, or 14-membered polycyclic heterocyclic ringwhich is saturated, partially unsaturated or fully unsaturated, andwhich consists of carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized to —NO—, —SO—, or —SO₂—. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. When the term “heterocycle” is used, it is intended toinclude heteroaryl.

Examples of heterocycles include, but are not limited to,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Preferred 5 to 10 membered heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Preferred 5 to 6 membered heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9 or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5 or 6-membered monocyclic aromatic ring comprising a 5 memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5 or 6 membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5 membered heterocycle, a 6 membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinoline, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxaline, and 1,2,3,4-tetrahydro-quinazoline.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean a stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Preferred heteroaryl groups are stable 5,6, or 7-membered monocyclic or 7, 8, 9, or 10-membered bicyclicheterocyclic aromatic rings which consists of carbon atoms and 1, 2, 3,or 4 heteroatoms independently selected from the group consisting of N,NH, O and S. It is to be noted that total number of S and O atoms in thearomatic heterocycle is not more than 1. Heteroaryl groups include,without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl,indolyl, pyrryl, oxazolyl, oxadiazolyl, benzofuryl, benzothienyl,benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl indazolyl,1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl,benzimidazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydrobenzothienyl-5-oxide, 2,3-dihydrobenzothienyl-5-dioxide,benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and thelike. Heteroaryl groups can be substituted or unsubstituted.

Also included are fused ring and spiro compounds containing, forexample, the above carbocycles or heterocycles.

Bridged rings are also included in the definition of carbocycle orheterocycle. A bridged ring occurs when one or more atoms (i.e., C, O,N, or S) link two non-adjacent carbon or nitrogen atoms. Preferredbridges include, but are not limited to, one carbon atom, two carbonatoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogengroup. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

The term “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, the disclosure of which is hereby incorporated by reference.

Isotopically labeled compounds of the present invention, i.e., whereinone or more of the atoms described are replaced by a radioactive isotopeof that atom (e.g., C replaced by ¹³C or by ¹⁴C; and isotopes ofhydrogen include tritium and deuterium), are also provided herein. Suchcompounds have a variety of potential uses, e.g., as standards andreagents in determining the ability of a potential pharmaceutical tobind to target proteins or receptors, or for imaging compounds of thisinvention bound to biological receptors in vivo or in vitro.

Compounds of the present invention are, subsequent to their preparation,preferably isolated and purified to obtain a composition containing anamount by weight equal to or greater than 98%, preferably 99%, compoundof the present invention (“substantially pure”), which is then used orformulated as described herein. Such “substantially pure” compounds arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), and    Methods in Enzymology, Vol. 42, at pp. 309-396, edited by K. Widder,    et. al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and    Application of Prodrugs,” by H. Bundgaard, at pp. 113-191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38    (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol.    77, p. 285 (1988); and-   e) N. Kakeya, et. al., Chem Phar Bull., Vol. 32, p. 692 (1984).

Preparation of Prodrugs is Well Known in the Art and Described in, forexample, Medicinal Chemistry: Principles and Practice, ed. F. D. King,The Royal Society of Chemistry, Cambridge, UK, 1994, which isincorporated herein by reference in its entirety.

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters which serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl, pivaloyloxymethyl orpropionyloxymethyl, C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g.methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl andother well known physiologically hydrolyzable esters used, for example,in the penicillin and cephalosporin arts. Such esters may be prepared byconventional techniques known in the art.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates and the like.Methods of solvation are generally known in the art.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination with other active ingredients to inhibit factorVIIa and/or plasma kallikrein or to treat the disorders listed herein.When applied to a combination, the term refers to combined amounts ofthe active ingredients that result in the therapeutic effect, whetheradministered in combination, serially or simultaneously. The combinationof compounds is preferably a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984,22:27-55, occurs when the effect (in this case, e.g., prevention ofthrombosis) of the compounds when administered in combination is greaterthan the additive effect of the compounds when administered alone as asingle agent. In general, a synergistic effect is most clearlydemonstrated at sub-optimal concentrations of the compounds. Synergy canbe in terms of lower cytotoxicity, increased antithrombotic and/oranti-inflammatory effect, or some other beneficial effect of thecombination compared with the individual components.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutical carrier. A “pharmaceutically acceptable carrier” refersto media generally accepted in the art for the delivery of biologicallyactive agents to animals, in particular, mammals, including, i.e.,adjuvant, excipient or vehicle, such as diluents, preserving agents,fillers, flow regulating agents, disintegrating agents, wetting agents,emulsifying agents, suspending agents, sweetening agents, flavoringagents, perfuming agents, antibacterial agents, antifungal agents,lubricating agents and dispensing agents, depending on the nature of themode of administration and dosage forms. Pharmaceutically acceptablecarriers are formulated according to a number of factors well within thepurview of those of ordinary skill in the art. These include, withoutlimitation: the type and nature of the active agent being formulated;the subject to which the agent-containing composition is to beadministered; the intended route of administration of the composition;and, the therapeutic indication being targeted. Pharmaceuticallyacceptable carriers include both aqueous and non-aqueous liquid media,as well as a variety of solid and semi-solid dosage forms. Such carrierscan include a number of different ingredients and additives in additionto the active agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 18th ed., 1990, which is incorporated herein by reference inits entirety.

Abbreviations used in the Examples are defined as follows: “1×” foronce, “2×” for twice, “3×” for thrice, “°C.” for degrees Celsius, “eq”for equivalent or equivalents, “g” for gram or grams, “mg” for milligramor milligrams, “L” for liter or liters, “mL” for milliliter ormilliliters, “μL” for microliter or microliters, “M” for molar, “mmol”for millimole or millimoles, “min” for minute or minutes, “h” for houror hours, “rt” for room temperature, “atm” for atmosphere, “psi” forpounds per square inch, “RT” for retention time, “sat” or “sat'd” forsaturated, “MW” for molecular weight, “MS” for mass spectrometry, “ESI”for electrospray ionization mass spectroscopy, “HR” for high resolution,“LC-MS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “NMR” for nuclear magnetic resonancespectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, “tlc” or “TLC” for thin layer chromatography, and“α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designationsfamiliar to one skilled in the art.

-   AcOH or HOAc is acetic acid,-   AIBN is azo-bis-isobutyrInitrile,-   BH₃.SMe₂ is borane-dimethyl sulfide complex,-   BH₃.THF is borane-tetrahydrofuran complex,-   BINAP is 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,-   Bn is benzyl,-   Boc is tert-butyl oxycarbonyl,-   BOP is benzotriazol-1-yloxy-tris(dimethylamino)phosphonium    hexafluorophosphate,-   Bu is butyl,-   iBu or i-Bu is isobutyl,-   t-Bu is tert-butyl,-   Cbz is carbonylbenzyloxy,-   CbzSerOtBu is (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic    acid tert-butyl ester,-   CDI is 1,1′-carbonyldiimidazole,-   CH₂Cl₂ is dichloromethane,-   CH₃CN is acetonitrile,-   Davis oxaziridine is 2-benzenesulfonyl-3-phenyl-oxaziridine,-   DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene,-   DCE is 1,2-dichloroethane,-   DIBAH is diisobutylaluminum hydride,-   DIC is 1,3-diisopropylcarbodiimde,-   DIEA is diethylpropyl amine,-   DMAP is dimethylaminopyridine,-   DMF is dimethylformamide,-   DMSO is dimethyl sulfoxide,-   DMPU is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone,-   DPPA is diphenylphosphoryl azide,-   EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,-   Et is ethyl,-   EtOAc is ethyl acetate,-   HATU is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium,-   HBTU is O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate,-   HCl is hydrochloric acid,-   HOAt or HOAT is 1-hydroxy-7-azabenzotriazole,-   HOBt or HOBT is 1-hydroxybenzotriaole,-   H₃PO₄ is phosphoric acid,-   K₂CO₃ is potassium carbonate,-   LAH is lithium aluminum hydride,-   LDA is lithium diisopropylamide,-   LiHMDS is bis(trimethylsilyl)amide,-   mCPBA or MCPBA is meta-chloroperbenzoic acid,-   Me is methyl,-   MeOH is methanol,-   MgSO₄ is magnesium sulfate,-   MoOPH is oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric    triamide),-   MsCl is methanesulfonyl chloride,-   Na is sodium,-   NaH is sodium hydride,-   NaHCO₃ is sodium bicarbonate,-   NaHSO₃ is sodium thiosulfite,-   NaOAc is sodium actetate,-   NBS is N-bromosuccinimide,-   NCS is N-chlorosuccinimide,-   OAc is acetate,-   Pd/C is palladium on carbon,-   Pd(PPh₃)₄ is tetraks (triphenylphosphine) palladium,-   Ph is phenyl,-   Pr is propyl,-   iPr or i-Pr is isopropyl,-   i-PrOH or IPA is isopropanol,-   PyBroP or Py-BroP is bromotripyrrolidinophosphonium    hexafluorophosphate,-   Selectfluor™ is    [1(chloromethy)-4-fluoro-1,4-diazoniabicyclo[2,2,2]octanebis(tetrafluoroborate)],-   TBAI is tetrabutylammonium iodide,-   tBME is tert-butyl methyl ether,-   TEA is triethylamine,-   TFA is trifluoroacetic acid,-   TFAA is trifluoroacetic anhydride,-   THF is tetrahydrofuran.    Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention.

A particularly useful compendium of synthetic methods which may beapplicable to the preparation of compounds of the present invention maybe found in Larock, R. C. Comprehensive Organic Transformations, VCH:New York, 1989. Preferred methods include, but are not limited to, thosedescribed below. All references cited herein are hereby incorporated intheir entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene and Wuts (Protective Groups In Organic Synthesis,Wiley-Interscience, 3nd Edition, 1999). All references cited herein arehereby incorporated in their entirety herein by reference.

Compounds having the general Formula (I):

wherein W, Y, R⁷-R⁹, R¹¹ and Z are each as defined above, can beprepared by coupling an acid of Formula (Ia):

with an amine of Formula (Ib):

under conditions suitable for forming an amide bond between the acid andthe amine. Coupling conditions can be found in Bodanszky, “Principles ofPeptide Synthesis, Second Edition” Springer Verlag Ed, Berlin (1993).Coupling reagents include CDI, DIC, and EDCI. Optionally, anintermediate activated ester can be prepared by adding one equivalent of1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole. Other couplingreagents include HATU, HBTU, and Py-Brop which are usually reacted inthe presence of one equivalent of a tertiary base such as DIEA or TEA.Protection and deprotection of functional groups may be required beforeor after the amide formation step to afford a compound of Formula (I).

The intermediate acids of Formula (Ia) can be prepared in severaldifferent ways. For example, they can be prepared according to the stepsdescribed in Scheme 1, where amines 1 (prepared following the methodsshown in later Schemes and in the Examples) react with phenyl acetatederivatives 2 (for preparation, see WO2004072101) under basic conditionsto give 3. LG is a leaving group such as Cl, Br, OMs (methylsulfonate)or OTf (trifluoromethylsulfonate) and P and P′ are protecting groups.Pyridyl acetate derivatives 2 can be prepared by methods known to oneskilled in the art. Deprotection of P in 3 by hydrolysis orhydrogenation gives acid intermediates Iaa containing a substituted1-aminoisoquinoline or 1-aminophthalazine group.

Acids Iaa wherein Y is a phenyl group can also be prepared by a Petasisboronic acid Mannich reaction (J. Am. Chem. Soc. 1997, 119, 445-446)shown in Scheme 2a. Amines 1 react with phenyl boronic acid derivatives4 and glyoxaldehyde 5 in a suitable solvent to give the acids Iaadirectly. This three component condensation reaction can be carried outthermally or under micro-wave irradiation. Preparation of boronic acids4 is well known to those skilled in the art (see Tetrahedron 2002, 58,9633-9695; Synthesis 2003, 4, 469-483). Acids Iaa wherein Y is a pyridylgroup can be prepared by reductive amination (Tetrahedron, 1996, 52,9777-9784) of pyridyl α-keto acids 6 with amines 1 as shown in Scheme2b. Pyridyl α-keto acids 6 can be prepared by methods known to oneskilled in the art.

Acids Iaa wherein Y is a phenyl group can also be prepared by reductiveamination (Tetrahedron, 1996, 52, 9777-9784) of α-keto acids 6 withamines 1 as shown in Scheme 3.

Alternatively to Schemes 1, 2a, 2b, and 3, as exemplified in Scheme 4a,acids Ia where W=isoquinolin-6-yl can be prepared from amino-esters 8.Amino-esters 8 can be accessed through a Strecker type synthesis, bycondensation of aldehydes 7 with trimethylsilylcyanide in presence ofammonia, followed by treatment with hydrochloric acid in MeOH. Compounds8 can be converted to 10 via coupling with aryl halides or sulfonates 9by methods known in the art. For example, amino-esters 8 may be coupledwith aryl halides 9 in the presence of a palladium catalyst, anappropriate ligand, for example, BINAP, and a base such as cesiumcarbonate to provide esters 10. Hydrolysis of 10 gives Iab.

Alternatively to Schemes 1 and 2, as exemplified in Scheme 4b, acids Iawhere W=isoquinolin-6-yl can be prepared from amino-esters 8. Aminoesters 8 can be accessed by several methods known in the art, includinga Strecker type synthesis, by condensation of pyridyl aldehydes 7 withtrimethylsilylcyanide in presence of ammonia, followed by treatment withhydrochloric acid in MeOH. Pyridyl aldehydes 7 are commerciallyavailable or can be synthesized by methods known to one skilled in theart. Compounds 8 can be converted to 10 via coupling with aryl halidesor sulfonates 9 by methods known in the art. For example, amino esters 8may be coupled to aryl halides 9 in the presence of a palladiumcatalyst, an appropriate ligand, for example, BINAP, and a base such ascesium carbonate to provide esters 10. Hydrolysis of 10 gives Iab.

Substituted isoquinoline amines 1 can be obtained from 11 as shown inScheme 5. Anilines 11 can be treated with an electrophilic source ofhalogens (Hal⁺), such as, for example, NCS, NBS or Selectfluor™.Bromides 12 can further be manipulated to provide anilines 1 whereinR⁶=alkyl, for example, via reaction with tetra-alkyltins in the presenceof a palladium catalyst such as PdCl₂(PPh₃)₃.

Substituted aminoisoquinoline amines 20 can be obtained from phenylhalides 13 as shown in Scheme 6. Phenyl halide anilines can be protectedwith appropriate protecting groups by methods known to those in the artto provide halides 13. These can be advanced by heating with an alkylcrotonates or alkyl acrylates 14 in the presence of a palladium catalystsuch as palladium (II) acetate and a ligand such as tri(o-tolyl)phosphine and a base such as triethylamine to give esters 15.Hydrolysis, followed by activation of the resulting acid as, forexample, a mixed anhydride, and treatment with an azide source, such assodium azide, yields acyl azides 16. Heating azides 16 at hightemperature in a solvent such as diphenyl ether, in the presence of anappropriate base such as tributylamine, provides isoquinolin-1(2H)-ones17. Treatment with phosphorous (III) oxychloride at reflux giveschlorides 18 which can be converted to the desired aminoisoquinolines 19by heating in a solution of ammonia in a solvent such as ethylene glycolin the presence of a catalyst such as copper (I) oxide. Appropriateprotection with, for example, excess di-tert-butyl dicarbonate, anddeprotection of the C-6 aniline in ways known in the art yieldsaminoisoquinolines 20.

These can be advanced to acids 22 by coupling with chlorides 21 in thepresence of a base such as DIPEA and heating, followed by deprotectionof the benzyl ester as shown in Scheme 6b.

Acid Ia wherein W is aminophthalazine-6-yl may be prepared according toScheme 7. 4-Bromobenzoic acid 23 is converted to the acid chloride andreacted with diethylamine. The resulting diethylbenzamide 24 isformylated by treatment with lithium tetramethylpiperidide at −78° C.,followed by quenching with DMF. Subsequent cyclization in refluxinghydrochloric acid provides the hydroxyphthalide 25. The hydroxyphthalide25 is refluxed with hydrazine in ethanol to afford 6-bromophthalazin-1(2H)-one 26. Treatment with phosphorous oxychloride gives6-bromo-1-chlorophthalazine 27, which is converted to1-amino-6-bromophthalazine 28 by reaction with ammonia saturatedethylene glycol at 130° C. The amine is protected by reaction withdi-tert-butyl dicarbonate and 4-dimethylaminopyridine in acetonitrile.The resulting bromide 29 can then by coupled with a phenylglycine ester30 with palladium-BINAP complex. Subsequent ester hydrolysis of ester 31gives acid 32.

Amines of Formula (Ib) are either commercially available or preparedaccording to the procedures given in the Schemes and Examples below.

In general, functionalized benzylamines 34, wherein R⁷═H, and Z is afunctionalized phenyl group, are prepared as exemplified in Scheme 8 viareduction of commercially available or prepared benzonitriles 33 (asshown in the Schemes and Examples below) via, for example, hydrogenationin the presence of a catalyst such as Pd/C or Raney Nickel, or using ahydride source, such as BH₃ or LAH in THF. Alternatively, as shown inScheme 9, benzylamines 34 can be prepared from esters 35 or aldehydes 36via reduction to benzyl alcohols 37 using, for example, LAH, followed byconversion to azides 38 with an appropriate reagent such asdiphenylphosphoryl azide in a solvent such as THF or toluene. Reductionof azides 38 with, for example, hydrogenation, LAH ortriphenylphosphine, provides benzylamines 34. Finally, as shown inScheme 10, benzylamines 34 can also be prepared from esters 35 viahydrolysis, treatment with ammonium hydroxide in the presence ofappropriate coupling reagents, such as EDC and HOBT or HOAT, followed byreduction of the derived primary amide with a hydride source, such asBH₃.

Amines of Formula (Ib), in which R⁷=alkyl and Z is a functionalizedphenyl group, can be prepared from benzylamines 34 as exemplified inScheme 11 via protection with, for example, trifluoroacetic anhydride togive 39, followed by alkylation with an alkyl halide, for example,methyl iodide. Deprotection with a base such as potassium carbonateyields the desired N-methyl benzylamines 41.

Benzylamines 44 containing an ortho-sulfone substituent can be prepared,as shown in Scheme 12, from sulfides 42, via oxidation to benzonitrilesulfones 43 with an appropriate oxidizing agent, such as MCPBA.Benzonitriles 43 can then be converted to the corresponding benzylamines44 as was previously shown in Scheme 8.

Sulfides 42 can be prepared in several different ways. As shown inScheme 13, one method involves advancing commercially availableo-bromobenzonitriles 45 via lithium-halogen exchange using, for examplen-butyl lithium at cold temperatures in a solvent such as THF followedby reaction with disulfides 46. Sulfides 42 can then be converted to thecorresponding benzylamines 44 by oxidation to the sulfones thenreduction to the benzylamines as was previously shown in Schemes 8 and12.

In addition, as shown in Scheme 14, sulfides 42 can also be preparedfrom o-cyanophenyldisulfides 47 by reaction with organometallicnucleophiles 48, for example, Grignard reagents. Sulfides 42 can then beconverted to the corresponding benzylamines 44 by oxidation to thesulfones then reduction benzylamines as was previously shown in Schemes8 and 12.

As shown in Scheme 15, sulfides 42 can also be prepared fromo-fluorobenzonitriles 49 via reaction with thiols 50 in a solvent suchas DMF in the presence of a base such as sodium carbonate. Sulfides 42can then be converted to the corresponding benzylamines 44 by oxidationto the sulfones then reduction benzylamines as was previously shown inSchemes 8 and 12. Also, sulfides 42 can be converted to benzylamines 51by treatment with a reducing agent, such as BH₃.

Finally, as shown in Scheme 16, sulfides 54 can be prepared fromthiosalicylates 52 via alkylation with alkyl halides 53, followed byoxidation to the sulfones 55 as was previously shown in Scheme 12. Theesters 55 can be converted to benzylamines 44 as was previously shown inScheme 9 or Scheme 10.

Benzylamines 58 containing a heterocyclic substituent can be prepared asshown in Scheme 17. Fluorobenzonitriles 49 are treated with amines 56 ina solvent such as acetonitrile. The resulting benzonitriles 57 are thenconverted to the benzylamines 58 as was previously shown in Scheme 8.

As shown in Scheme 18, benzylamines 62 containing an ortho-sulfonamidesubstituent can be prepared from o-cyano sulfonyl chlorides 59 viareaction with amines 60 (or amine hydrochloride salts) in the presenceof a base, for example, TEA, in a solvent such as THF or water.Benzonitriles 61 can then be converted to the corresponding benzylamines62 as was previously shown in Scheme 8.

Benzylamines 65 containing an amide substituent can be derived fromcyanobenzoic acids 63 as shown in Scheme 19, by treatment of acids 63with amines 60 (or amine hydrochloride salts) in the presence ofappropriate coupling reagents such as EDC, HOAT and a base such as DIEA.The derived benzonitriles 64 can then be converted to the benzylamines65 as was previously shown in Scheme 8. Alternatively, amides 65 can beprepared as shown in Scheme 20 from isobenzofuran-1(3H)-ones 66 bytreatment with amines 60 in the presence of trimethylaluminum. Thederived benzyl alcohols 67 can then be converted to the correspondingbenzylamines as was previously shown in Scheme 9.

Benzylamines 71 containing an ortho-ether substituent can be prepared,as shown in Scheme 21, from phenols 68, via alkylation with alkylhalides 69. The derived benzonitriles 70 can then be converted to thecorresponding benzylamines 71 as was previously shown in Scheme 8.

Functionalized benzylamines 76 containing an alkyl substituent can beprepared, as shown in Scheme 22, from benzaldehydes 72, via Wittigreaction with alkyltriphenylphosphonium halides 73 in the presence of abase, such as potassium tert-butoxide. The derived olefins 74 can thenbe converted to the corresponding unsaturated benzylamines 75 using ahydride source such as BH₃, or to the saturated benzylamines 76 viahydrogenation in the presence of a catalyst, such as Pd/C.

As exemplified in Scheme 23, functionalized benzylamines 81 and 83containing acetamide or carbamate substituents can be prepared fromnitro compounds 77 via reduction to the anilines 78 with, for example,iron. Anilines 78 can be treated with anhydrides 79 to provideacetamides 80, or with alkyl chloroformates 82 to give carbamates 83.These benzonitrile products 80 and 83 can then be converted to thedesired benzylamines 81 and 84 as was previously shown in Scheme 8.

As shown in Scheme 24, chiral β-aminoesters 89 can be prepared by aconjugate addition of lithium (S)-(−)—N-benzy-N-α-methylbenzamides toα,β-unsaturated esters 87 which in turn can be prepared by condensationof the aldehydes 85 and diethylphosphonate esters 86. The conjugatedadduct 88 can be hydrogenated with a catalyst such as Pd(OH)₂/C to giveenantiomerically enriched β-aminoesters 89.

Alternatively, aldehydes 85 (Scheme 25) can be condensed with(S)-(+)-toluene sulfinamide 90 in the presence of catalyst such asTi(OEt)₄ to the sulfinylimines 91. Addition of metal enolates 92 to thesulfinylimine 91 should proceed stereoselectively to give thesulfinamides 93 which can be deprotected under acidic conditions toβ-aminoesters 89.

The compound of the instant invention herein described may haveasymmetric centers. For example, the chiral carbon atom in Formula (I)or (IV) as indicated below, exists in either S or R configuration.

Possibly, a second chiral carbon atom exists when R⁸ and R⁹ aredifferent. Thus, the stereoisomeric configurations of each compound ofthe present invention are considered part of the invention. For example,but not limited to therein, in compounds of Formula (II), the followingtwo stereoisomeric configurations are possible:

For example, but not limited to therein, in compounds of Formula (V),the following two stereoisomeric configurations are possible:

They are collectively, as well as individually, considered part of theinvention. In a preferred stereoisomeric embodiment, the presentinvention provides for a stereoisomeric configuration of isomer-1 forall embodiments of Formula (I), (II) or (III); a stereoisomericconfiguration of isomer-3 for all embodiments of Formula (IV), (V) or(VI); or tautomer, pharmaceutically acceptable salt, solvate, or prodrugform thereof.

In the following experimental procedures, solution ratios express avolume relationship, unless stated otherwise. NMR chemical shifts (δ)are reported in parts per million.

Products were analyzed by reverse phase analytical HPLC carried out on aShimadzu Analytical HPLC system running DiscoveryVP software usingMethod A: Phenomenex Luna C18 column (4.6×50 mm or 4.6×75 mm) eluted at4 mL/min with a 4 or 8 min gradient from 100% A to 100% B (A: 10%methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA,UV 220 nm), or Method B: Phenomenex Luna C18 column (4.6×50 mm) elutedat 4 mL/min with a 4 min gradient from 100% A to 100% B (A: 10%acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile,0.1% TFA, UV 220 mm). Purification of intermediates and final productswas carried out via either normal or reverse phase chromatography.Normal phase chromatography was carried out on an ISCO CombiFlash™System using prepacked SiO₂ cartridges eluted with gradients of hexanesand ethyl acetate. Reverse phase preparative HPLC was carried out usinga Shimadzu Preparative HPLC system running DiscoveryVP software usingMethod A: YMC Sunfire 5 μm C18 30×100 mm column with a 10 min gradientat 40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1%TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm), Method B:Phenomenex AXIA Luna 5 μm C18 30×75 mm column with a 10 min gradient at40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1%TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm), Method C:Phenomenex Luna 5 μm C18 30×100 mm column with a 10 min gradient at 40mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1%TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm), or MethodD: Phenomenex Luna 5 μm C18 30×100 mm column with a 10 min gradient at40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA;B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm). LCMS chromatogramswere obtained on a Shimadzu HPLC system running DiscoveryVP software,coupled with a Waters ZQ mass spectrometer running MassLynx version 3.5software using the same columns and conditions as utilized foranalytical described above.

EXAMPLES

The following examples have been prepared, isolated and characterizedusing the methods disclosed herein. The following examples demonstrate apartial scope of the invention and are not meant to be limiting of thescope of the invention.

Synthesis of Common Intermediates Intermediate 16-Amino-1-di-tert-butoxycarbonylaminoisoquinoline

Intermediate 1A (E)-2-(2-(Dimethylamino)vinyl)-4-nitrobenzonitrile

A mixture of compound 2-methyl-4-nitrobenzonitrile (Aldrich, 5.0 g, 31mmol) and 1-(1,1-dimethylethoxy)-N,N,N′,N′-tetramethyl-methanediamine(Aldrich, 12.2 mL, 59 mmol) in dry DMF (8 mL) was stirred at 70° C. for2 h under N₂. After cooling to rt, DMF was removed in vacuo and thecrude product was triturated with hexanes/ethyl acetate (5:1). The solidwas collected by filtration and washed with hexane to give Intermediate1A (6.5 g, 97% yield) as black solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.97(s, 6H) 5.36 (d, J=13.18 Hz, 1H) 7.16 (d, J=13.62 Hz, 1H) 7.52 (d,J=8.79 Hz, 1H) 7.60 (m, 1H) 8.11 (d, J=1.76 Hz, 1H).

Intermediate 1B 2-(2,4-Dimethoxybenzyl)-6-nitroisoquinolin-1(2H)-imine

Intermediate 1A (4.6 g, 21.2 mmol) and 2,4-dimethoxylbenzylamine (4.0mL, 1.25 equiv) in DMPU (10 mL) was heated at 140° C. for 3 h. Thesolvent was removed by vacuum distillation and residue treated withhexanes/ethyl acetate (1:1). The solid was collected by filtration andwashed with hexane to give Intermediate 1B (4.6 g). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.72 (s, 3H) 3.81 (s, 3H) 4.96 (s, 1H) 6.28 (d, J=6.59Hz, 1H) 6.46 (d, J=7.47 Hz, 1H) 6.58 (d, J=1.76 Hz, 1H) 7.03 (d, J=8.79Hz, 1H) 7.27 (d, J=6.15 Hz, 1H) 8.02 (dd, J=9.01, 2.42 Hz, 1H) 8.31 (d,J=2.20 Hz, 1H) 8.43 (d, J=8.35 Hz, 1H).

Intermediate 1C 6-Nitroisoquinolin-1-amine

To a solution of Intermediate 1B (11.9 g, 35 mmol) in anisole (24 mL)was added TFA (24 mL). The reaction mixture was stirred at 90° C. for 6h and the solvent removed under reduced pressure. The residue wassuspended in MeOH (50 mL) and then treated with NaHCO₃ (3.3 g, 39 mmol)in water (200 mL). The mixture was stirred at rt for 15 min and pH waschecked to be ca 8.0. Most of the methanol was removed in vacuo. Theprecipitate was collected by filtration and washed with water to affordIntermediate 1C (6.0 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.20 (d, J=5.721H) 7.36 (s, 2H) 7.95 (d, J=5.72 Hz, 1H) 8.15 (dd, J=9.24, 2.64 Hz, 1H)8.43 (d, J=9.24 Hz, 1H) 8.67 (d, J=2.64 Hz, 1H).

Intermediate 1D 6-Nitro-1-di-tert-butoxycarbonylaminoisoquinoline

A mixture of Intermediate 1C (50 mg) and di-tert-butyl dicarbonate (200mg) was heated at 120° C. for 1.0 h. The crude residue was purified byflash chromatography (25% EtOAc/hexanes) to afford 78 mg (78% yield) ofIntermediate 1D as a solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.33 (s, 18H)7.86 (d, J=5.27 Hz, 1H) 8.15 (d, J=9.23 Hz, 1H) 8.39 (dd, J=9.23, 2.20Hz, 1H) 8.62 (d, J=5.71 Hz, 1H) 8.82 (d, J=2.20 Hz, 1H). LC-MS: 801(2M+Na).

Intermediate 1 6-Amino-1-di-tert-butoxycarbonylaminoisoquinoline

Intermediate 1D (55 mg) in methanol (2.5 mL) was hydrogenated with ahydrogen balloon in the presence of Pd/C (10%, 35 mg) for 2.0 h.Filtration of the Pd/C and concentration gave Intermediate 1 as a whitesolid (47 mg, 92%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.33 (m, 18H) 4.18 (s,2H) 6.89 (d, J=2.20 Hz, 1H) 6.99 (dd, J=9.01, 2.42 Hz, 1H) 7.35 (d,J=6.59 Hz, 1H) 7.75 (d, J=8.79 Hz, 1H) 8.22 (d, J=5.71 Hz, 1H). LC-MS:741 (2M+Na).

Intermediate 22-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid

Intermediate 2A 2-Isopropoxyphenyl acetate

To a solution of 2-isopropoxyphenol (1.53 g, 10 mmol) in CH₂Cl₂ at 0°C., pyridine (1.76 mL, 22 mmol) was added and followed by acetylchloride (0.79 mL, 1.1 eq). The mixture was stirred at 0° C. for 1.0 h,diluted with diethyl ether, washed with 5% citric acid and brine. Theorganic extract was dried over Na₂SO₄, evaporated to give Intermediate2A as an oil. It was used for next step without further purification.

Intermediate 2B 5-Iodo-2-isopropoxyphenyl acetate

To a solution of Intermediate 2A (10 mmol) in CH₂Cl₂ at 0° C., iodinemonochloride (1.0 M in CH₂Cl₂, 11.0 mL) was added dropwise in 20 min.The mixture was stirred at 0° C. for 2.0 h, diluted with ether, washedwith saturated Na₂S₂O₃ and brine. The organic extract was dried overMgSO₄, evaporated to give Intermediate 2B as an oil. It was used fornext step without further purification.

Intermediate 2C 5-Iodo-2-isopropoxyphenol

To a solution of Intermediate 2B (10 mmol) in MeOH (5 mL) and THF (15mL), LiOH (1.0 M, 15 mL) was added at 0° C. After the mixture wasstirred at rt for 3.0 h, 5% citric acid (30 mL) and diethyl ether (150mL) was added. The organic extract was washed with brine, dried overNa₂SO₄ and evaporated to give Intermediate 2C (2.3 g) as an oil.

Intermediate 2D 2-Ethoxy-4-iodo-1-isopropoxybenzene

To a solution of Intermediate 2C (2.3 g, 8.3 mmol) in DMF (20 mL) K₂CO₃(2.3 g, 16.5 mmol) and ethyl iodide (0.86 mL, 10.8 mmol) were added. Themixture was stirred at 40° C. for 2.0 h. It was diluted with diethylether, washed with brine, dried over MgSO₄. The crude was purified bychromatography (5:1 EtOAc/hexanes) to give Intermediate 2D (2.5 g, 96%yield) as an oil.

Intermediate 2E 3-Ethoxy-4-isopropoxyphenylboronic acid

To a solution of Intermediate 2D (2.39 g, 7.8 mmol) in THF (25 mL) at−78° C., n-BuLi (1.6 M in hexanes, 6.83 mL, 1.4 eq) was slowly added.The reaction mixture was stirred at −78° C. for 20 min, followed byaddition of triisopropyl borate (4.95 mL, 21.5 mmol). The mixture wasstirred at −78° C. for 3.0 h and then warm up to rt over 1.0 h. It wasquenched by addition of 5% citric acid (20 mL), followed by a solutionof Na₂S₂O₃. After extraction with EtOAc, drying over Na₂SO₄, the crudewas purified by chromatography to give Intermediate 2E (1.2 g, 67%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.41 (d, J=6.15Hz, 6H) 1.49 (t, J=7.03 Hz, 3H) 4.21 (q, J=7.03 Hz, 2H) 4.64 (m, 1H)7.02 (d, J=8.35 Hz, 1H) 7.70 (s, 1H) 7.79 (m, 1H).

Intermediate 22-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid

A mixture of Intermediate 2E (308 mg, 1.38 mmol), Intermediate 1 (494mg, 1.38 mmol) and glyoxylic acid monohydrate (127.1 mg, 1.38 mmol) intoluene (12 mL) and methanol (2.5 mL) was heated at 60° C. for 6.0 h andthen stirred at rt over night. After removing solvent, the crude waspurified by chromatography eluting with CH₂Cl₂/MeOH to give Intermediate2 (0.65 g, 78% yield) as a yellow solid. ¹H NMR (400 MHz, Methanol-d₄) δppm 1.29 (m, 24H) 1.35 (t, J=7.03 Hz, 3H) 4.05 (dd, J=7.03, 5.27 Hz, 2H)4.49 (m, 1H) 5.11 (s, 1H) 6.68 (d, J=1.76 Hz, 1H) 6.93 (d, J=8.35 Hz,1H) 7.10 (dd, J=8.35, 2.20 Hz, 1H) 7.17 (d, J=1.76 Hz, 1H) 7.27 (dd,J=9.23, 2.20 Hz, 1H) 7.42 (d, J=5.71 Hz, 1H) 7.62 (d, J=9.23 Hz, 1H)8.01 (d, J=6.15 Hz, 1H).

Intermediate 32-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid hydrochloride

Intermediate 2 (1.04 g, 1.75 mmol) was dissolved in ethyl acetate (26mL) and was treated with a 4N HCl solution in 1,4-dioxane (26 mL, 105mmol). After stirring at rt overnight, the reaction was concentrated,diluted with diethyl ether and filtered to provide Intermediate 3 (747mg) as a yellow solid. ¹H NMR (400 MHz, d6-DMSO) δ ppm 1.22 (d, J=7.03Hz, 6H), 1.30 (t, J=7.03 Hz, 3H), 4.00 (q, J=7.03 Hz, 2H), 4.37-4.53 (m,2H), 5.19-5.33 (m, 1H), 6.75 (s, 1H), 6.81 (d, J=7.03 Hz, 1H), 6.90-7.04(m, 2H), 7.13 (d, J=2.20 Hz, 1H), 7.24 (d, J=8.79 Hz, 1H), 7.43 (dd,1H), 7.43 (dd, J=7.03, 5.71 Hz, 1H), 7.63 (s, 1H), 8.20 (d, J=9.23 Hz,1H), 8.50 (s, 2H), 12.52 (d, J=5.27 Hz, 1H). LC-MS: 396.30 (M+H)⁺.

Intermediate 42-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)aceticacid

A mixture of 3,4-dimethoxyphenyl boronic acid (457 mg, 2.5 mmol),Intermediate 1 (900 mg, 2.5 mmol) and glyoxylic acid monohydrate (231mg, 2.5 mmol) in toluene (20 mL) and methanol (2.5 mL) was heated at 50°C. for 3.0 h and then stirred at rt over night. After removing solvent,the crude was purified by chromatography eluting with CH₂Cl₂/MeOH.Intermediate 4 (1.18 g, 85%) was obtained as a yellow solid. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.27 (s, 18H) 3.79 (s, 3H) 3.81 (s, 3H) 5.07 (s,1H) 6.67 (d, J=2.20 Hz, 1H) 6.92 (d, J=8.35 Hz, 1H) 7.13 (m, 1H) 7.18(d, J=1.76 Hz, 1H) 7.26 (dd, J=9.23, 2.20 Hz, 1H) 7.41 (d, J=6.15 Hz,1H) 7.62 (d, J=9.23 Hz, 1H) 8.00 (d, J=5.71 Hz, 1H).

Intermediate 5 3-(Aminomethyl)benzenesulfonamide

Intermediate 5A 3-Cyanobenzenesulfonamide

To 3-cyanobenzene sulfonyl chloride (0.37 g, 1.81 mmol) in THF (3 mL),ammonium hydroxide (28% in water, 0.13 g, 3.62 mmol) was added. Thereaction was stirred at rt for 30 min. Water was added and the productwas extracted with EtOAc. After drying over Na₂SO₄, the solvent wasevaporated to give 0.3 g of Intermediate 5A a white solid.

Intermediate 5 3-(Aminomethyl)benzenesulfonamide

To Intermediate 5A (0.3 g, 1.65 mmol) in methanol (8 mL) under nitrogen,10% Pd/C (0.1 g) was added and then a balloon filled with hydrogen gaswas introduced. The reaction was stirred for 3.0 h at rt. The catalystwas filtered off and the solvent was removed to give Intermediate 5(0.29 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.79 (m, 2H) 7.47 (t, J=7.58Hz, 1H) 7.53 (m, 1H) 7.65 (d, J=7.58 Hz, 1H) 7.81 (s, 1H).

Intermediate 6 (2-(Methylsulfonyl)phenyl)methanamine

Intermediate 6A 2-(Methylsulfonyl)benzonitrile

To a solution of MCPBA (75%, 7.8 g, 31.6 mmol) and NaHCO₃ (3.0 g, 35.8mmol) in CH₂Cl₂ (150 mL), 2-methylthiobenzonitrile (2.14 g, 14.3 mmol)in CH₂Cl₂ (50 mL) was added at 0° C. The mixture was stirred at 0° C.for 30 min, then at rt over night. After filtration, the organic phasewas washed with brine, dried over Na₂SO₄. Intermediate 6A was obtainedas a slightly yellow solid after removal of solvent. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 3.22 (s, 3H) 7.83 (m, 2H) 7.96 (m, 1H) 8.11 (d,J=7.91 Hz, 1H).

Intermediate 6 (2-(Methylsulfonyl)phenyl)methanamine

To a solution of Intermediate 6A (181 mg, 1.0 mmol) in MeOH (10 mL),Pd/C (10% by weight, 50 mg) and 4.0 N HCl in dioxane (0.5 mL, 2.0 mmol)were added. This mixture was hydrogenated with a H₂ balloon for 4.0 h.After filtration and concentration, Intermediate 6 was obtained as HClsalt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.33 (s, 3H) 4.42 (s, 2H) 7.69 (m,1H) 7.81 (m, 2H) 8.00 (d, J=7.47 Hz, 1H) 8.56 (s, 3H).

Intermediate 7 (2-(Cyclopropylsulfonyl)phenyl)methanamine HydrochlorideSalt

Intermediate 7A 2-(Cyclopropylsulfonyl)benzonitrile

To 2,2′-dithio-bis(benzonitrile) (obtained from Sumitomo Seika) (2.00 g,7.46 mmol) in THF (37 mL) at −78° C., a 0.5 M THF solution ofcyclopropyl magnesium bromide (149 mL, 74.6 mmol) was added via additionfunnel. After 10 min, the reaction was quenched with saturated aqueousammonium chloride (200 mL). After warming to rt, the reaction productwas diluted with water and ethyl acetate and the layers were separated.The organic layer was washed with water and brine, dried (MgSO₄),filtered and concentrated. The resulting residue was purified via silicagel chromatography eluting with 15% ethyl acetate/hexane to provide2-(cyclopropylthio)benzonitrile as a yellow oil (1.36 g). The oil wasdissolved in CH₂Cl₂, ˜75% MCPBA (6.00 g, 26.1 mmol) was added and thereaction was stirred at rt for 2 h. 1N NaOH was added and the layerswere separated. The organic layer was washed with 1N NaOH (3×) and brine(1×) then dried (MgSO₄), filtered and concentrated to provideIntermediate 7A (1.50 g, 97% yield, 2 steps) as a white solid.

Intermediate 7 (2-(Cyclopropylsulfonyl)phenyl)methanamine HydrochlorideSalt

To Intermediate 7A (1.50 g, 7.25 mmol) in refluxing THF (72 mL), a 2MTHF solution of BH₃.SMe₂ (10.8 mL, 21.7 mmol) was added. After heatingat reflux for 2 h, the reaction was cooled to rt and 6M HCl (4.32 mL)was slowly added. The reaction was heated to reflux for 30 min, thencooled to rt, concentrated and azeotroped (3×) with THF/MeOH on a rotaryevaporator. The resulting residue was taken up in THF and filtered toprovide Intermediate 7 (1.40 g, 79%) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ ppm 1.15 (m, 2H) 1.29 (m, 2H) 2.91 (m, 1H) 4.52 (s, 2H) 7.72(m, J=7.69, 7.69 Hz, 2H) 7.80 (t, J=6.81 Hz, 1H) 8.04 (d, J=7.91 Hz,1H).

Intermediate 8 (2-(Cyclopropylsulfonyl)phenyl)-N-methylmethanaminehydrochloride

Intermediate 8AN-(2-(Cyclopropylsulfonyl)benzyl)-2,2,2-trifluoroacetamide

To Intermediate 7 (1.16 g, 4.70 mmol) in CH₂Cl₂ (47 mL) at 0° C. wasadded DIPEA (1.60 mL, 9.40 mmol) followed by trifluoroacetic anhydride(3.30 mL, 23.5 mmol). After stirring (0° C. to rt) for 1.5 h, thereaction was concentrated. The resulting residue was dissolved in ethylacetate, washed with water and brine, dried (MgSO₄), filtered andconcentrated to provide Intermediate 8A (1.68 g) as a yellow oil. LC-MS:307.93 (M+H)⁺

8B N-(2-(Cyclopropylsulfonyl)benzyl)-2,2,2-trifluoro-N-methylacetamide

To Intermediate 8A (1.68 g, 5.47 mmol) in CH₃CN (55 mL) was addedpotassium carbonate (1.13 g, 8.20 mmol), tetrabutylammonium bromide (88mg, 0.27 mmol) and methyl iodide (3.40 mL, 54.7 mmol) and the reactionwas heated to reflux overnight. After cooling to rt and concentrating,the remaining residue was dissolved in ethyl acetate and washed withwater (3×) and brine. The organic layer was dried (MgSO₄), filtered andconcentrated to provide Intermediate 8B (1.50 g) as a yellow oil. LC-MS:321.95 (M+H)⁺.

Intermediate 8 (2-(Cyclopropylsulfonyl)phenyl)-N-methylmethanaminehydrochloride

To Intermediate 8B (1.50 g, 4.67 mmol) in MeOH (23 mL) and water (5 mL)was added potassium carbonate (3.20 g, 23.4 mmol) and the reaction wasrefluxed for 45 min. After cooling to rt, the mixture was filtered andthe filtrate was concentrated. The resulting residue was dissolved inethyl acetate and washed with water and brine. The aqueous layer wasback-extracted with ethyl acetate (5×). The combined organic layers weredried (MgSO₄), filtered and concentrated to provide a yellow oil. Theoil was dissolved in THF and 4N HCl in 1,4-dioxane (2.2 mL) was added.The resulting white solid was filtered to provide Intermediate 8 (1.00g). ¹H NMR (400 MHz, CD₃OD) δ ppm 1.03-1.21 (m, 2H), 1.30 (ddd, J=7.14,4.50, 4.17 Hz, 2H), 2.80 (s, 3H), 2.84-3.03 (m, 1H), 2.86-3.05 (m, 1H),4.41-4.65 (m, 2H), 7.59-7.93 (m, 3H), 8.06 (d, J=7.91 Hz, 1H). LC-MS:226.10 (M+H)⁺.

Intermediate 9 N-(3-(Aminomethyl)-4-(ethylsulfonyl)phenyl)acetamide

Intermediate 9A 2-(Ethylthio)-5-nitrobenzonitrile

To 2-fluoro-5-nitrobenzonitrile (5.00 g, 30.1 mmol) in DMF (100 mL),triethylamine (9.30 mL, 66.7 mmol) was added and followed by ethanethiol(2.80 mL, 37.9 mmol). After stirring at rt for 1 h, the reaction mixturewas poured into water (500 mL). The resulting precipitate was filteredand dried on high vacuum overnight to provide Intermediate 9A (6.08 g,97%).

Intermediate 9B 2-(Ethylsulfonyl)-5-nitrobenzonitrile

To Intermediate 9A (6.08 g, 29.2 mmol) in CH₂Cl₂ (100 mL), 75% MCPBA(16.0 g, 69.5 mmol) was added. After stirring at rt overnight, thereaction product was washed with saturated aqueous NaHCO₃, 1M H₃PO₄ andbrine then dried (Na₂SO₄), filtered and concentrated. The resultingresidue was purified via silica gel chromatography eluting with 10-35%ethyl acetate/hexane to provide Intermediate 9B (6.20 g, 88%). LC-MS:209.20 (M+H)⁺.

Intermediate 9C N-(3-Cyano-4-(ethylsulfonyl)phenyl)acetamide

To Intermediate 9B (3.60 g, 15.0 mmol) in 1:1 acetic acid/aceticanhydride (150 mL), Fe (4.20 g, 75.2 mmol) was added. The reactionmixture was heated to 100° C. for 2 h then poured into ice. After theice melted, the product was extracted with ethyl acetate, and theorganic layer was washed with saturated aqueous NaHCO₃ and brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated to provideIntermediate 9C (3.14 g, 83%). LC-MS: 241.18 (M+H)⁺.

Intermediate 9 N-(3-(Aminomethyl)-4-(ethylsulfonyl)phenyl)acetamide

To Intermediate 9C (423 mg, 1.65 mmol) in MeOH (17 mL), Raney Ni (cat)was added. The whole mixture was stirred under hydrogen (60 psi) for 8h. The reaction product was filtered and concentrated to provideIntermediate 9 (397 mg, 92%). LC-MS: 253.23 (M+H)⁺.

Intermediate 10N-(4-(Ethylsulfonyl)-3-((methylamino)methyl)phenyl)acetamidetrifluoroacetic acid salt

Intermediate 10AN-(4-(Ethylsulfonyl)-3-((methylamino)-2,2,2-trifluoroacetamide)-phenyl)acetamide

A solution of Intermediate 9 (100 mg, 0.39 mmol) in trifluoroaceticanhydride (5 mL) was stirred at rt for 30 min. The reaction was pouredinto ice, and after the ice melted, the product was extracted with ethylacetate. The organic layer was washed with brine, dried (Na₂SO₄),filtered and concentrated. The resulting residue was purified via silicagel chromatography eluting with 10-60% ethyl acetate/hexanes to provideIntermediate 10A (45 mg). LC-MS: 353.11 (M+H)⁺.

Intermediate 10BN-(4-(Ethylsulfonyl)-3-((methylamino)-2,2,2-trifluoroacetamide-N-methyl)-phenyl)acetamide

To a mixture of 60% NaH (4.8 mg, 0.12 mmol) in DMF (1 mL) was added asolution of Intermediate 10A (41 mg, 0.12 mmol) in DMF (1.5 mL). Afterstirring at rt for 1 h, a solution of methyl iodide (17 mg, 0.12 mmol)in DMF (0.5 mL) was added and the reaction was heated to 80° C.overnight. The reaction was cooled to rt and concentrated. The resultingresidue was purified via preparative HPLC eluting with MeOH/water/TFA toprovide Intermediate 10B (38 mg).

Intermediate 10N-(4-(Ethylsulfonyl)-3-((methylamino)methyl)phenyl)acetamidetrifluoroacetic acid salt

To Intermediate 10B (38 mg, 0.10 mmol) in MeOH (3 mL) was addedpotassium carbonate (42 mg, 0.30 mmol) in water (0.5 mL). The reactionwas heated to reflux for 1 h, then was cooled to rt and concentrated.The resulting residue was purified via preparative HPLC eluting withCH₃CN/water/TFA to provide Intermediate 10 (31 mg). ¹H NMR (400 MHz,CD₃OD) δ ppm 1.26 (t, J=7.25 Hz, 3H), 2.18 (s, 3H), 2.78 (s, 3H),3.23-3.36 (m, 3H), 4.43 (s, 2H), 7.80 (dd, J=8.79, 2.20 Hz, 1H), 7.99(d, J=8.79 Hz, 1H), 8.11 (d, J=2.20 Hz, 1H). LC-MS: 271.16 (M+H)⁺.

Intermediate 11 (2-(Cyclobutylsulfonyl)phenyl)methanamine hydrochloride

Intermediate 11A Methyl 2-(cyclobutylsulfonyl)benzoate

To methylthiosalicylate (3.92 mL, 28.5 mmol) in DMF at 0° C. was addedtriethylamine (3.97 mL, 28.5 mmol) then cyclobutyl bromide (5.00 g, 37.0mmol). The ice bath was removed and the reaction was stirred at rt for 1h then heated to 50° C. overnight. After cooling to rt, diethyl etherwas added and the mixture was filtered. The filtrate was diluted withethyl acetate, then washed with water (6×) and brine (1×). The organiclayer was dried (MgSO₄), filtered and concentrated to provide a yellowoil. The yellow oil was dissolved in CH₂Cl₂ (143 mL) and MCPBA (˜75%,19.7 g, ca. 85.5 mmol) was added. The reaction was stirred for 2.5 h,then was cooled to 0° C. 1 N NaOH was added, and the whole was stirredfor 5 min. The layers were separated, and the organic layer was washedwith 1 N NaOH (2×). The aqueous layer was back-extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried (MgSO₄),filtered and concentrated to provide Intermediate 11A as a clear oil(7.20 g). LC-MS: 255.01 (M+H)⁺.

Intermediate 11B 2-(Cyclobutylsulfonyl)benzoic acid

To Intermediate 11A (7.20 g, 28.3 mmol) in THF (190 mL) was added 1 NLiOH (94 mL). The reaction was stirred for 1 h at rt, then was heatedgradually to 65° C. After cooling to rt, the THF was removed underreduced pressure. The remaining solution was cooled to 0° C. andacidified to pH 1 with 1N HCl. The product was extracted with CH₂Cl₂,and the organic layer was washed with brine, dried (MgSO₄), filtered andconcentrated to provide Intermediate 11B as a clear oil (6.30 g). LC-MS:241.08 (M+H)⁺.

Intermediate 11C 2-(Cyclobutylsulfonyl)benzamide

To Intermediate 11B (6.30 g, 26.2 mmol) in DMF (52.5 mL) was addedHOBT.H₂O (4.9 g, 32.0 mmol) and EDC (5.98 g, 31.3 mmol). After stirring1 h at rt, the reaction was cooled to 0° C. and 25% ammonium hydroxidewas added. The reaction was stirred for 1.5 h and was then diluted withethyl acetate/THF and washed with 1N HCl (2×) and 1 N NaOH (2×). Theaqueous layer was back-extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried (MgSO₄), filtered andconcentrated to provide Intermediate 11C (5 g) as a yellow solid. LC-MS:240.08 (M+H)⁺.

Intermediate 11 (2-(Cyclobutylsulfonyl)phenyl)methanamine hydrochloride

To Intermediate 11C (5.00 g, 20.9 mmol) in THF (80 mL) at reflux wasadded a 1M THF solution of BH₃.THF (63 mL, 62.7 mmol) via an additionfunnel, dropwise over 20 min. After refluxing for 6 h, additionalBH₃.THF solution was added (20 mL) and refluxing continued overnight.After cooling to rt, 6N HCl (12.5 mL) was added and the reaction washeated again to reflux for 1 h. The reaction was cooled to rt,concentrated then azeotroped (3×) with MeOH/THF. After drying undervacuum for 1 h, the resulting residue was taken up in THF and filteredto provide Intermediate 11 as a white solid. ¹H NMR (400 MHz, CD₃OD) δppm 1.94-2.11 (m, 2H), 2.13-2.26 (m, 2H), 2.43-2.61 (m, 2H), 4.11-4.23(m, 1H), 4.43 (s, 2H), 7.66-7.76 (m, 2H), 7.81 (t, J=6.81 Hz, 1H), 8.03(d, J=6.15 Hz, 1H). LC-MS: 226.11 (M+H)⁺.

Intermediate 12 (2-(Cyclobutylsulfonyl)phenyl)-N-methylmethanaminehydrochloride

Intermediate 12AN-(2-(Cyclobutylsulfonyl)benzyl)-2,2,2-trifluoroacetamide

To Intermediate 11 (3.20 g, 12.3 mmol) in CH₂Cl₂ (61.5 mL) at 0° C. wasadded DIPEA (4.70 mL, 27.0 mmol) followed by trifluoroacetic anhydride(8.70 mL, 61.5 mmol). After stirring (0° C. to rt) for 30 min, thereaction was concentrated. The resulting residue was diluted with ethylacetate, washed with water (2×) and brine, dried (MgSO₄), filtered andconcentrated to provide Intermediate 12A (4.70 g) as an oily solid.LC-MS: 343.95 (M+23)⁺.

Intermediate 12BN-(2-(Cyclobutylsulfonyl)benzyl)-2,2,2-trifluoro-N-methylacetamide

To Intermediate 12A (4.70 g, 14.6 mmol) in CH₃CN (73 mL) was addedpotassium carbonate (3.03 g, 21.9 mmol), tetrabutylammonium bromide (470mg, 1.46 mmol) and methyl iodide (9.09 mL, 146 mmol) and the reactionwas heated to 80° C. overnight. After cooling to rt and concentrating,the remaining residue was dissolved in ethyl acetate and washed withwater (2×) and brine. The aqueous layer was back-extracted with ethylacetate and the combined organic layers were dried (MgSO₄), filtered andconcentrated to provide Intermediate 12B (4.70 g) as a yellow oil.LC-MS: 335.96 (M+H)⁺.

Intermediate 12 (2-(Cyclobutylsulfonyl)phenyl)-N-methylmethanaminehydrochloride

To Intermediate 12B (4.70 g, 14.0 mmol) in MeOH (70 mL) and water (5 mL)was added potassium carbonate (9.70 g, 70.0 mmol) and the reaction wasrefluxed for 45 min. After cooling to rt, the reaction was filtered andthe filtrate was concentrated. The resulting residue was dissolved inethyl acetate and washed with water (2×). The aqueous layer wasback-extracted with ethyl acetate. The combined organic layers weredried (MgSO₄), filtered and concentrated to provide a yellow solid (3.20g). The solid was dissolved in THF and conc. HCl was added (1.1 mL).Intermediate 12 (3.20 g) was obtained after concentrating and dryingunder vacuum. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.93-2.12 (m, 2H), 2.13-2.27(m, 2 H), 2.43-2.59 (m, 2H), 4.11-4.24 (m, 1H), 4.49 (s, 2H), 7.70-7.86(m, 3H), 8.05 (d, J=7.91 Hz, 1H). LC-MS: 240.12 (M+H)⁺.

Intermediate 132-(3-Ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)acetic AcidHydrochloric Acid Salt

Intermediate 13A 2-Amino-2-(3-ethoxy-4-isopropoxyphenyl)acetonitrileHydrochloric Acid Salt

3-Ethoxy-4-isopropoxybenzaldehyde (WO 2004072101) (24 g, 115 mmol) wasdissolved in a 7N MeOH solution of ammonia (200 mL) and the whole wascooled to 0° C. Trimethylsilyl cyanide (24 mL, 180 mmol) was added andthe reaction mixture was stirred overnight with gradual warming to rt.The reaction product was concentrated to provide2-amino-2-(3-ethoxy-4-isopropoxyphenyl)acetonitrile (29 g, 100%) as ayellow oil. The oil (23 g) was dissolved in ethyl ether (460 mL), cooledto 0° C., and HCl (g) was bubbled through the solution for 5 min. Theresulting precipitate was filtered and dried on the high vac to provideIntermediate 13A (19 g, 72%) as a yellow solid.

Intermediate 13B Methyl 2-amino-2-(3-ethoxy-4-isopropoxyphenyl)acetate

Intermediate 13A (4.00 g, 14.8) was dissolved in MeOH (74 mL) and cooledto 0° C. HCl (g) was bubbled through the system for 20 min which causeda solid to precipitate. The ice bath was removed and the reactionmixture was warmed to rt for 45 min. Water (300 μL) was added and thereaction was heated to reflux. After 5 h, the reaction product wascooled to rt and concentrated. Water and ethyl acetate were added andthe layers were separated. The organic layer was washed with saturatedaqueous sodium bicarbonate and brine, dried (MgSO₄), filtered andconcentrated and purified via silica gel chromatography (eluting with50-75% ethyl acetate in hexane, then 100% ethyl acetate, then 2%MeOH/ethyl acetate) to provide Intermediate 13B (4.00 g, 82%) as a brownoil. LC-MS: 268.2 (M+H)⁺.

Intermediate 13C Methyl2-(3-ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)acetate

Intermediate 13B (172 mg, 0.640 mmol), 6-bromoisoquinoline (140 mg,0.670 mmol), cesium carbonate (626 mg, 1.92 mmol), racemic BINAP (20.0mg, 0.0321 mmol) and Pd₂(dba)₃ (10 mg, 0.0109 mmol) were combined in atube and the whole was degassed for 5 min with nitrogen. Toluene (3 mL)was added and the reaction was sealed and heated to 100° C. for 20 h.After cooling to rt, the reaction product was diluted with ethyl acetateand was washed with brine. The organic layer was dried (Na₂SO₄),filtered and concentrated. The resulting residue was purified via silicagel chromatography (eluting with 10-90% ethyl acetate in hexane) toprovide Intermediate 13C (182 mg). LC-MS: 395.20 (M+H)⁺.

Intermediate 132-(3-Ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)acetic AcidHydrochloric Acid Salt

Intermediate 13C (406 mg, 1.03 mmol) was dissolved in THF (10 mL) and a1 M aqueous LiOH solution (3 mL) was added. The reaction was stirred atrt for 1 h and was then concentrated. The residue was dissolved in water(20 mL) and was washed with ethyl acetate (2×10 mL). The aqueous layerwas acidified with 1 N HCl to provide a yellow precipitate. The wholewas cooled in an ice bath then filtered and dried to provideIntermediate 13 (230 mg). LC-MS: 381.18 (M+H)⁺.

Intermediate 14 (2-(Isopropylsulfonyl)benzylamine Hydrochloride Salt

Intermediate 14A 2-(Isopropylsulfonyl)benzonitrile

To 2-bromobenzonitrile (728 mg, 4.00 mmol) in THF (20 mL) at −78° C. wasadded a 1.9M solution of n-BuLi in hexanes (2.31 mL, 4.4 mmol). Afterstirring at the same temperature for 1 h, diisopropyl disulfide (782 mg,5.20 mmol) in THF (10 mL) was added and the reaction was stirred at −78°C. for 1 h, then at rt overnight. The reaction was quenched withsaturated aqueous ammonium chloride and was allowed to warm to rt. Ethylacetate and water were added and the layers were separated. The organiclayer was washed with brine, then was dried (Na₂SO₄), filtered andconcentrated to provide a yellow oil (1.04 g). The oil (354 mg, 2.00mmol) was dissolved in CH₂Cl₂ and ˜75% MCPBA (2.20 g) was added. Afterstirring at rt for 30 min, the reaction was diluted with ethyl acetateand washed with saturated aqueous NaHCO₃ and brine, dried (Na₂SO₄),filtered then concentrated to provide Intermediate 14A (150 mg). LC-MS:210.19 (M+H)⁺.

Intermediate 14 (2-(Isopropylsulfonyl)benzylamine Hydrochloride Salt

To Intermediate 14A (116 mg, 0.554 mmol) in methanol (10 mL), conc. HCl(146 mg) was added and followed by 10% Pd/C (15 mg). The mixture washydrogenated at 30 psi for 2 h. The reaction product was filtered andconcentrated to provide Intermediate 14 (135 mg, 98%). LC-MS: 214.1(M+H)⁺.

Intermediate 152-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)aceticacid

Intermediate 15A 4-Bromo-1-chloro-2-ethoxybenzene

To a solution of 2-chloro-5-bromophenol (WO98/03464, 3.43 g, 16.5 mmol)and K₂CO₃ (4.57 g, 33.0 mmol) in DMF (20 mL) was added ethyl iodide(1.78 mL, 22.3 mmol) at rt. The mixture was heated at 55° C. for 3.0 h.After cooled to rt, it was diluted with ether, washed with water andbrine, dried over MgSO₄. The crude residue was purified by flash columnchromatography to give 3.85 g (99%) of Intermediate 15A as viscous oil.¹H NMR (400 MHz, CDCl₃) δ ppm 1.48 (t, J=7.03 Hz, 3H) 4.08 (d, J=7.03Hz, 2H) 7.03 (m, 2H) 7.22 (d, J=6.15 Hz, 2H).

Intermediate 15B 4-Chloro-3-ethoxyphenylboronic acid

To a solution of Intermediate 15A (3.8 g, 16 mmol) in THF (20 mL) at−78° C. was added n-BuLi (1.6 M in hexanes, 13.6 mL, 21.8 mmol). Themixture was stirred at −78° C. for 40 min before triisopropyl borate(7.43 mL, 32 mmol) was added. The reaction was left stirring from −78°C. to rt over 18 h. It was quenched with 1.0 N HCl (50 mL), extractedwith EtOAc, washed with brine and dried over Na₂SO₄. The crude residuewas purified by flash column chromatography (CH₂Cl₂:EtOAc:MeOH=50:50:1)to give 1.85 g (57%) of Intermediate 15B as a white solid. ¹H NMR (400MHz, CDCl₃) δ ppm 1.53 (t, J=7.03 Hz, 3H) 4.23 (d, J=7.03 Hz, 2H) 7.48(d, J=7.91 Hz, 1H) 7.66 (d, J=6.15 Hz, 2H).

Intermediate 152-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)aceticacid

A mixture of Intermediate 15B (46 mg, 0.23 mmol), Intermediate 1 (72 mg,0.2 mmol) and glyoxylic acid monohydrate (21 mg, 0.23 mmol) in1,2-dichloroethane (0.8 mL) was heated at 100° C. for 5 min. in aMicrowave Reactor. The crude product was purified by flash columnchromatography (CH₂Cl₂:MeOH=100:15) to give 57 mg (50%) of Intermediate15 as a solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.29 (s, 18H) 1.32(t, J=7.03 Hz, 3H) 4.10 (m, 2H) 5.52 (s, 1H) 6.81 (s, 1H), 7.21 (d,J=7.91 Hz, 1H) 7.21 (s, 1H), 7.37 (d, J=7.91 Hz, 1H) 7.50 (m, 1H), 7.69(d, J=7.91 Hz, 1H) 7.96 (d, J=7.91 Hz, 1H) 8.00 (d, J=7.91 Hz, 1H) LC MS572 (M+H).

Intermediate 16(1-Di-tert-butoxycarbonylamino-isoquinolin-6-ylamino)-(3-ethoxy-phenyl)-aceticacid

A mixture of 3-ethoxyphenylboronic acid (45 mg, 0.27 mmol), Intermediate1 (72 mg, 0.20 mmol) and glyoxylic acid monohydrate (26 mg, 0.28 mmol)in 1,2-dichloroethane (2 mL) was heated at 100° C. for 12.5 min. in amicrowave reactor. The crude product was purified by flash columnchromatography (gradient from 0-20% methanol in dichloromethane) to give60 mg (56%) of Intermediate 16 as a solid. LC-MS m/z: 538.3 (M+H)⁺.

General Coupling-Deprotection Procedure:

Most of the final compounds described in the following examples weremade according to the following general coupling-deprotection scheme:

A mixture of intermediate acid (1 eq, preparation given in examples),amine (1.5-8 eq, commercial available or otherwise noted withpreparation), EDCI (2-4 eq), HOAT (0.4-3 eq), DIEA (0-8 eq) in CH₂Cl₂(0.01M) or CH₂Cl₂/DMF (0.03 M, 10:1) was stirred at rt for 4 h toovernight. The reaction product was concentrated and purified viapreparative HPLC (MeOH/H₂O/TFA or CH₃CN/H₂O/TFA) to provide the desireddi-Boc-protected amide. To a solution of the amide (1 eq) in EtOAc(˜0.04 M) was added a 4 M solution of HCl in dioxane (˜100 eq) and thereaction was stirred at rt for 4 h to overnight. The reaction productwas then concentrated and purified via preparative HPLC (MeOH/H₂O/TFA orCH₃CN/H₂O/TFA) then lyophilized (CH₃CN, H₂O) to provide the desiredfinal compound as a solid TFA salt. The yields of the final TFA saltswere in the range of 15-85%.

Example 1N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 1 was prepared according to the general coupling-deprotectionusing Intermediate 2 and commercial N-(3-(aminomethyl)phenyl)acetamideHCl salt. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.21 (d, J=6.15 Hz, 6H)1.28 (t, J=7.03 Hz, 3H) 2.00 (s, 3H) 3.90 (q, J=7.03 Hz, 2H) 4.29 (m,2H) 4.44 (m, 1H) 4.97 (s, 1H) 6.56 (s, 1H) 6.70 (d, J=7.03 Hz, 1H) 6.81(d, J=7.03 Hz, 1H) 6.87 (d, J=8.35 Hz, 1H) 6.99 (m, 2H) 7.08 (m, 2H)7.25 (m, 2H) 7.36 (s, 1H) 7.99 (d, J=9.23 Hz, 1H) 8.73 (t, J=5.71 Hz,1H). LC-MS 542 (M+H).

Example 2(R)-N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamide

Example 2 (41 mg) was separated from the racemic mixture (120 mg) ofExample 1 using a semi-preparative HPLC equipped with a Chiralpak®OJ-Hcolumn (2 cm×25m, 5 g). The separation was performed using an isocraticmethod of 20% ethanol/methanol (1:1) in heptane with 0.1% diethylamineand a flow rate of 20 mL/min. Retention time for Example 2 was 22 min.The retention time for the other isomer (43 mg) was 28 min. LC-MS 542(M+H).

Example 3N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 3 was prepared according to the general coupling-deprotectionusing Intermediate 4 and commercial N-(3-(aminomethyl)phenyl)acetamideHCl salt. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 2.00 (s, 3H) 3.70 (s, 3H)3.74 (s, 3H) 4.28 (dd, J=5.93, 2.42 Hz, 1H) 4.98 (s, 1H) 6.56 (d, J=1.76Hz, 1H) 6.70 (d, J=7.47 Hz, 1H) 6.82 (d, J=7.47 Hz, 1H) 6.87 (m, 1H)7.07 (m, 3H) 7.26 (m, 3H) 7.99 (d, J=8.79 Hz, 1H) 8.73 (t, J=5.93 Hz,1H). LC-MS 500 (M+H).

Example 4(R)-N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetamide

Example 4 (34 mg) was separated from the racemic mixture (100 mg) ofExample 3 using a semi-preparative HPLC equipped with a Chiralpak®OJ-Hcolumn (2 cm×25 m, 5 g). The separation was performed using an isocraticmethod of 35% ethanol/heptane with 0.1% diethylamine and a flow rate of20 mL/min. Retention time of Example 4 was 24 min. Retention time of theother isomer (41 mg) was 38 min. LC-MS 500 (M+H).

Example 5[2-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetylamino]-(3-sulfamoyl-phenyl)-aceticacid trifluoroacetic acid salt

5A N-tert-Butyl-3-(hydroxymethyl)benzenesulfonamide

To a solution of 3-tert-butylsulfamoyl-benzoic acid (5.15 g, 20 mmol, J.Med. Chem. 1999, 42, 515-525) in THF (100 mL) at −20° C. was addedN-methyl morpholine (2.97 mL, 1.35 eq) and ethyl chloroformate (2.11 mL,1.1 eq). The mixture was stirred between −20 to −10° C. for 30 min. ThenNaBH₄ (1.13 g, 1.5 eq) was added, followed by slow addition of MeOH (20mL). After stirring at −20° C. for 40 min, the reaction was quenched byaddition of 5% citric acid. After removal of solvent, the crude wasdiluted with EtOAc, washed with 5% NaHCO₃ and dried over Na₂SO₄.Evaporation of solvent gave 5A as a white solid.

5B N-tert-Butyl-3-formylbenzenesulfonamide

To a solution of 5A (4.4 g, 18 mmol) in CH₂Cl₂ (80 mL) at 0° C., NaHCO₃(1.8 g, 1.2 eq) and Dess-Martin periodinane (7.64 g, 18 mmol) wereadded. The mixture was stirred at rt for 2.0 h before it was dilutedwith EtOAc and washed with water and brine. The extract was dried overNa₂SO₄ and the crude was purified by chromatography eluting with 1:3EtOAc/hexanes to give 5B (3.9 g, 89% yield).

5C Amino-(3-tert-butylsulfamoyl-phenyl)-acetic acid methyl ester

To a solution of 5B (190 mg, 0.79 mmol) in 7.0 N NH₃ in MeOH (4.0 mL),trimethylsilyl cyanide (0.28 mL, 2.1 mmol) was added at 0° C. Themixture was stirred at rt over night. Solvent was removed in vacuo togive the corresponding amino nitrile. The amino nitrile was dissolved inMeOH (5.0 mL) and treated with 4.0 N HCl/dioxane (5.18 mL, 10 eq) at rtfor 3.0 h, reflux for 8.0 h. After removal of solvent, 5C was obtainedwith sufficient purity for next step.

5D Amino-(3-sulfamoyl-phenyl)-acetic acid methyl ester

5C (150 mg, 0.5 mmol) was treated with anisole (0.16 mL, 3.0 eq) and TFA(2.5 mL) at rt over night. After removal of solvent in vacuo, the crudewas dissolved in MeOH (3.0 mL) and treated with basic resin (WA215 fromSupelco) at rt for 1.0 h until pH>7. Filtration and evaporation ofsolvent gave 5D as an oil. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.21 (m,6H) 1.28 (m, 3H) 3.94 (m, 2H) 4.44 (m, 1H) 5.14 (d, J=15.38 Hz, 1H) 5.51(d, J=12.30 Hz, 1H) 6.60 (dd, J=41.74, 2.20 Hz, 1H) 6.74 (dd, J=38.67,7.03 Hz, 1H) 6.87 (m, 1H) 7.02 (m, 3H) 7.22 (t, J=7.47 Hz, 1H) 7.32 (d,J=5.71 Hz, 1H) 7.51 (m, 1H) 7.76 (m, 2H) 7.98 (t, J=9.01 Hz, 1H).

5E

Example 5 (5 mg) was prepared according to the generalcoupling-deprotection using Intermediate 2 (25 mg) and 5D (20 mg)followed by saponification of the methyl ester (13 mg) using 4.0equivalents of LiOH (1.0 M in H₂O) in THF for 5.0 h. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.21 (m, 6H) 1.28 (m, 3H) 3.94 (m, 2H) 4.44 (m, 1H)5.14 (d, J=15.38 Hz, 1H) 5.51 (d, J=12.30 Hz, 1H) 6.60 (dd, J=41.74,2.20 Hz, 1H) 6.74 (dd, J=38.67, 7.03 Hz, 1H) 6.87 (m, 1H) 7.02 (m, 3H)7.22 (t, J=7.47 Hz, 1H) 7.32 (d, J=5.71 Hz, 1H) 7.51 (m, 1H) 7.76 (m,2H) 7.98 (t, J=9.01 Hz, 1H). LC-MS 608 (M+H).

Example 62-(2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)-2-phenylaceticacid trifluoroacetic acid salt

Example 6 was prepared according to the general coupling-deprotectionusing Intermediate 2 and phenylglycine methyl ester followed bysaponification of the methyl ester as in procedure 5E. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.21 (dd, J=5.93, 2.86 Hz, 6H) 1.28 (m, 3H) 3.90 (q,J=6.88 Hz, 1H) 3.96 (q, J=7.03 Hz, 1H) 4.43 (m, 1H) 5.14 (m, 1H) 5.42(m, 1H) 6.76 (m, 3H) 7.03 (m, 3H) 7.17 (m, 3H) 7.27 (m, 3H) 7.98 (dd,J=9.01, 5.05 Hz, 1H) 8.81 (m, 1H). LC-MS 529(M+H).

Example 72-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-(3-sulfamoyl-benzyl)-acetamidetrifluoroacetic acid salt

Example 7 was prepared according to the general coupling-deprotectionusing Intermediate 2 and Intermediate 5. ¹H NMR (400 MHz, Methanol-d₄) δppm 1.30 (d, J=6.15 Hz, 6H) 1.37 (t, J=7.03 Hz, 3H) 4.02 (m, 2H) 4.47(d, J=2.64 Hz, 2H) 4.54 (m, 1H) 5.07 (s, 1H) 6.65 (d, J=2.20 Hz, 1H)6.81 (d, J=7.03 Hz, 1H) 6.98 (d, J=8.35 Hz, 1H) 7.08 (m, 2H) 7.18 (dd,J=9.01, 2.42 Hz, 1H) 7.32 (d, J=7.03 Hz, 1H) 7.38 (m, 2H) 7.75 (m, 1H)7.78 (s, 1H) 8.08 (d, J=9.23 Hz, 1H). LC-MS 564 (M+H).

Example 8(R)-2-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-(3-sulfamoyl-benzyl)-acetamidetrifluoroacetic acid salt

Example 8 (48 mg) was separated from the racemic mixture (100 mg) ofExample 7 using a preparative HPLC equipped with a Chiralpak® AD column(5 cm×50 cm, 20μ). The separation was performed using an isocraticmethod of 30% ethanol/isopropanol (1:1) in heptane with 0.1%trifluoroacetic acid and a flow rate of 50 mL/min. Retention time forExample 8 was 70 min. LC-MS 564 (M+H).

Example 92-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-(2-sulfamoyl-benzyl)-acetamidetrifluoroacetic acid salt

9A 2-(Aminomethyl)benzenesulfonamide

To 2-cyanobenzenesulfonamide (213 mg, 1.2 mmol) in methanol (5.0 mL) wasadded 10% Pd/C (50 mg) and 4.0 M HCl in dioxane (0.6 mL, 2.4 mmol). Themixture was stirred under a hydrogen balloon at rt overnight andfiltrated. The filtrate was concentrated to a colorless oil of 9A as HClsalt (200 mg, 80% yield). ¹H NMR (400 MHz, Methanol-d₄) δ ppm 4.34 (s,2H) 7.43-7.57 (m, 3H) 7.91 (d, J=7.91 Hz, 1H).

9B

Example 9 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 9A. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.21(d, J=6.15 Hz, 6H) 1.28 (t, J=7.03 Hz, 3H) 3.89 (m, 2H) 4.45 (m, 1H)4.78 (m, 2H) 5.01 (s, 1H) 6.58 (d, J=2.20 Hz, 1H) 6.74 (d, J=7.03 Hz,1H) 6.88 (d, J=7.91 Hz, 1H) 6.97 (m, 2H) 7.10 (dd, J=9.23, 2.20 Hz, 1H)7.20 (m, 1H) 7.28 (m, 2H) 7.82 (m, 1H) 7.99 (d, J=9.23 Hz, 1H) 8.54 (m,1H). LC-MS 564 (M+H).

Example 10N-(3-Hydroxybenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 10 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 3-(aminomethyl)phenol. ¹H NMR (400 MHz,Methanol-d₄) ppm 1.20 (t, J=5.49 Hz, 6H) 1.28 (t, J=7.03 Hz, 3H) 3.91(q, J=7.03 Hz, 2H) 4.23 (d, J=3.08 Hz, 2H) 4.44 (m, 1H) 4.97 (s, 1H)6.55 (m, 4H) 6.73 (d, J=7.47 Hz, 1H) 6.87 (d, J=8.35 Hz, 1H) 6.95 (m,2H) 7.01 (d, J=1.76 Hz, 1H) 7.10 (dd, J=9.01, 2.42 Hz, 1H) 7.23 (d,J=7.47 Hz, 1H) 7.99 (d, J=9.23 Hz, 1H). LC-MS 501 (M+H).

Example 11N-(3-Aminobenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 11 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 3-(aminomethyl)benzenamine. ¹H NMR (400 MHz,Methanol-d₄) (ppm 1.29 (d, J=6.15 Hz, 6H) 1.36 (t, J=7.03 Hz, 3H) 4.00(q, J=7.03 Hz, 2H) 4.40 (d, J=5.71 Hz, 2H) 4.52 (m, 1H) 5.09 (s, 1H)6.67 (d, J=2.20 Hz, 1H) 6.82 (d, J=7.03 Hz, 1H) 6.96 (d, J=8.35 Hz, 1H)7.06 (m, 5H) 7.19 (dd, J=9.23, 2.64 Hz, 1H) 7.26 (t, J=7.91 Hz, 1H) 7.33(d, J=7.03 Hz, 1H) 8.09 (d, J=9.23 Hz, 1H) 8.89 (m, 1H). LC-MS 500(M+H).

Example 123-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenylboronicacid trifluoroacetic acid salt

Example 12 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 3-(aminomethyl)phenylboronic acid. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.22 (d, J=6.15 Hz, 6H) 1.28 (t, J=6.81 Hz, 3H)3.90 (m, J=5.71 Hz, 2H) 4.33 (m, 2H) 4.44 (dd, J=12.30, 6.15 Hz, 1H)4.97 (s, 1H) 6.57 (s, 1H) 6.70 (d, J=7.03 Hz, 1H) 6.87 (d, J=7.91 Hz,1H) 6.99 (m, 2H) 7.12 (m, 3H) 7.24 (d, J=7.03 Hz, 1H) 7.39 (m, 2H) 7.99(d, J=9.23 Hz, 1H) 8.75 (d, J=6.15 Hz, 1H); LC-MS 529 (M+H).

Example 133-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)benzamidetrifluoroacetic acid salt

Example 13 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 3-(aminomethyl)benzamide. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.21 (d, J=6.15 Hz, 6H) 1.28 (t, J=6.81 Hz, 3H) 3.92(m, 2H) 4.37 (d, J=5.71 Hz, 2H) 4.44 (m, 1H) 6.57 (d, J=1.76 Hz, 1H)6.70 (d, J=7.03 Hz, 1H) 6.88 (d, J=8.35 Hz, 1H) 6.98 (m, 2H) 7.09 (dd,J=9.23, 2.20 Hz, 1H) 7.24 (m, 3H) 7.64 (m, 2H) 7.99 (d, J=8.79 Hz, 1H)8.81 (t, J=5.93 Hz, 1H). LC-MS 528 (M+H).

Example 14N-(3-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 14 was prepared according to the general coupling-deprotectionusing Intermediate 2 and (3-(methylsulfonyl)phenyl)methanamine. ¹H NMR(400 MHz, Methanol-d₄) δ ppm 1.22 (d, J=6.15 Hz, 6H) 1.29 (t, J=6.81 Hz,3H) 3.93 (q, J=6.74 Hz, 2H) 4.36 (dd, J=15.16, 5.49 Hz, 1H) 4.47 (m, 2H)5.00 (s, 1H) 6.57 (d, J=1.76 Hz, 1H) 6.73 (d, J=7.03 Hz, 1H) 6.89 (d,J=8.35 Hz, 1H) 7.00 (m, 2H) 7.10 (dd, J=9.23, 2.20 Hz, 1H) 7.24 (d,J=7.03 Hz, 1H) 7.41 (m, 2H) 7.69 (m, 2H) 8.00 (d, J=9.23 Hz, 1H) 8.88(t, J=5.93 Hz, 1H). LC-MS 563 (M+H).

Example 172-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-(indolin-4-ylmethyl)acetamidetrifluoroacetic acid salt

17A Indolin-4-ylmethanamine

To 1H-indole-4-carbonitrile (284 mg, 2.0 mmol) in MeOH (10 mL), 4.0 NHCl/dioxane (1.25 mL, 2.5 eq) and 10% Pd/C (200 mg) were added. Themixture was hydrogenated with a H₂ balloon for 48 h. Filtration andevaporation of solvent gave 17A as HCl salt. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 3.45 (t, J=7.69 Hz, 2H) 3.92 (t, J=7.69 Hz, 2H) 4.22(s, 2H) 7.57 (m, 5H).

17B

Example 17 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 17A. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.21(d, J=6.15 Hz, 6H) 1.28 (t, J=7.03 Hz, 3H) 2.81 (s, 1H) 3.00 (m, 1H)3.56 (t, J=8.13 Hz, 2H) 3.93 (q, J=6.88 Hz, 2H) 4.36 (m, 3H) 5.01 (m,1H) 6.74 (d, J=7.03 Hz, 1H) 6.90 (m, 2H) 6.98 (m, 1H) 7.08 (m, 4H) 7.25(d, J=7.03 Hz, 1H) 8.00 (d, J=9.23 Hz, 1H) 8.75 (t, J=5.93 Hz, 1H).LC-MS 526 (M+H).

Example 18 (2S)-tert-Butyl2-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)-2-phenylacetatetrifluoroacetic acid salt

Example 18 was prepared according to the general coupling-deprotectionusing Intermediate 2 and (S)-tert-butyl 2-amino-2-phenylacetate. ¹H NMR(400 MHz, Methanol-d₄) δ ppm 1.25 (m, 18H) 3.91 (q, J=7.03 Hz, 1H) 3.97(q, J=7.03 Hz, 1H) 4.43 (dd, J=11.21, 5.05 Hz, 1H) 5.13 (d, J=4.83 Hz,1H) 5.30 (t, J=3.74 Hz, 1H) 6.65 (m, 2H) 6.93 (m, 3H) 7.18 (m, 7H) 7.99(dd, J=9.23, 4.39 Hz, 1H) 8.79 (m, 1H). LC-MS 585 (M+H).

Example 192-(1-Amino-isoquinolin-6-ylamino)-N-(3,5-disulfamoyl-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

19A Methyl 3,5-bis(chlorosulfonyl)benzoate

To a solution of 3,5-bis(chlorosulfonyl)benzoyl chloride (100 mg, 0.3mmol, WO2001010838) in CH₂Cl₂ (1.5 mL) at 0° C. was added MeOH (0.026mL, 2.2 eq). The mixture was stirred at rt for 3.0 h. After removal ofsolvent in vacuo, 19A was obtained as a white solid.

19B 3,5-Bis-tert-butylsulfamoyl-benzoic acid methyl ester

To a solution of 19A (0.3 mmol) in CH₂Cl₂ (2.0 mL) was addedtert-butylamine (0.095 mL, 0.9 mmol) and diisopropyl ethylamine (0.21mL, 4.0 eq). The mixture was stirred at rt over night. It was dilutedwith EtOAc, washed with 5% citric acid, brine and dried over MgSO₄.After removal of solvent, the crude was purified by chromatographyeluting with 2:3 EtOAc/hexanes to give 19B (98 mg, 81% yield).

19C N1,N3-di-tert-Butyl-5-(hydroxymethyl)benzene-1,3-disulfonamide

To a solution of 19B (98 mg, 0.24 mmol) in THF (1.5 mL), LiBH₄ (2.0 M inTHF, 0.21 mL, 1.75 eq) was added. The mixture was stirred at rt overnight, diluted with EtOAc, quenched with 5% citric acid. Theorganic-extract was washed with brine, dried over Na₂SO₄. After removalof solvent in vacuo, 19C (90 mg, 94% yield) was obtained as an oil.

19D 5-(Azidomethyl)-N1,N3-di-tert-butylbenzene-1,3-disulfonamide

To a solution of 19C (90 mg, 0.23 mmol) in THF (1.5 mL), diphenylphosphoryl azide (0.062 mL, 1.25 eq) and DBU (0.043 mL, 1.25 eq) wereadded. The mixture was stirred at rt over night. The product wasdirectly purified by chromatography eluting with 1:2 EtOAc/hexanes togive 19D (80 mg, 85% yield) as a solid.

19E 5-(Aminomethyl)-N1,N3-di-tert-butylbenzene-1,3-disulfonamide

A mixture of 19D (538 mg) and 10% Pd/C (650 mg) in MeOH (10 mL) washydrogenated with a H₂ balloon for 3.0 h at rt. Filtration andevaporation of solvent gave 19E.

19F 5-(Aminomethyl)benzene-1,3-disulfonamide

19E was treat with trifluoroacetic acid over night. After removal oftrifluoroacetic acid in vacuo, the residue was suspended in DMF andtreated with basic resin (WA215 from Supelco, 2.5 g) for 1.0 h untilpH>7. Filtration and evaporation of solvent gave 19F contaminated withca 8% of the mono-deprotection product5-aminomethyl-benzene-1,3-disulfonic acid 1-amide 3-tert-butylamide(19F′). ¹H NMR (400 MHz, Methanol-d₄) (ppm 4.21 (m, 2H) 7.98 (m, 1H)8.15 (d, J=1.76 Hz, 2H).

19G

Example 19 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 19F. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.21(d, J=6.15 Hz, 6H) 1.29 (t, J=7.03 Hz, 3H) 3.94 (q, J=7.03 Hz, 2H) 4.45(m, 3H) 4.97 (s, 1H) 6.50 (d, J=1.76 Hz, 1H) 6.69 (d, J=7.03 Hz, 1H)6.89 (d, J=8.35 Hz, 1H) 6.98 (m, 2H) 7.08 (dd, J=9.23, 2.20 Hz, 1H) 7.20(d, J=7.03 Hz, 1H) 7.86 (d, J=1.76 Hz, 2H) 7.98 (d, J=9.23 Hz, 1H) 8.16(s, 1H) 8.93 (m, 1H). LC-MS 643 (M+H).

Example 202-(1-Amino-isoquinolin-6-ylamino)-N-(3-tert-butylsulfamoyl-5-sulfamoyl-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 20 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 19F′. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.02(s, 9H) 1.21 (d, J=6.15 Hz, 6H) 1.29 (t, J=7.03 Hz, 3H) 3.95 (m, 2H)4.45 (m, 3H) 4.96 (s, 1H) 6.50 (d, J=2.20 Hz, 1H) 6.70 (d, J=7.47 Hz,1H) 6.89 (d, J=8.35 Hz, 1H) 6.98 (m, 2H) 7.07 (dd, J=9.23, 2.64 Hz, 1H)7.20 (d, J=7.03 Hz, 1H) 7.86 (d, J=12.74 Hz, 2H) 7.98 (d, J=9.23 Hz, 1H)8.13 (s, 1H) 8.95 (s, 1H). LC-MS 699 (M+H).

Example 21N-(3-(Methylsulfonamido)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

21A N-(3-(Aminomethyl)phenyl)methanesulfonamide

21A was prepared according to the procedure given in J. Med. Chem. 2003,46, 3116-3126.

21B

Example 21 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 21A. LC-MS 578 (M+H).

Example 22N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 22 was prepared according to the general coupling-deprotectionusing Intermediate 2 and Intermediate 6. ¹H NMR (400 MHz, Methanol-d₄) δppm 1.29 (d, J=6.15 Hz, 6H) 1.36 (t, J=7.03 Hz, 3H) 3.15 (s, 3H) 3.99(m, 2H) 4.53 (m, 1H) 4.71 (dd, J=15.82, 5.71 Hz, 1H) 4.82 (d, J=6.15 Hz,1H) 5.10 (s, 1H) 6.65 (d, J=2.20 Hz, 1H) 6.80 (d, J=7.03 Hz, 1H) 6.96(d, J=8.35 Hz, 1H) 7.06 (m, 2H) 7.18 (dd, J=9.23, 2.20 Hz, 1H) 7.33 (m,2H) 7.47 (m, 2H) 7.91 (m, 1H) 8.07 (d, J=9.23 Hz, 1H) 8.68 (t, J=6.15Hz, 1H). LC-MS 563 (M+H).

Example 23 Methyl2-((2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)benzoatetrifluoroacetic acid salt

23A Methyl 2-(aminomethyl)benzoate

To a solution of methyl 2-cyanobenzoate (322 mg, 2.0 mmol)) in MeOH (6mL), Pd/C (10% by weight, 61 mg) and 4.0 N HCl in dioxane (0.875 mL,1.75 eq) were added. This mixture was hydrogenated with a H₂ balloon for2.0 h. After filtration and concentration, 23A was obtained as HCl salt.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.86 (s, 3H) 4.30 (d, J=5.71 Hz, 2H)7.55 (m, 1H) 7.65 (m, 2H) 7.99 (d, J=7.91 Hz, 1H) 8.49 (s, 3H).

23B

Example 23 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 23A. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.28(t, J=6.81 Hz, 6H) 1.36 (t, J=7.03 Hz, 3H) 3.75 (s, 3H) 3.98 (m, 2H)4.52 (m, 1H) 4.64 (m, 1H) 4.73 (m, 1H) 5.06 (s, 1H) 6.58 (d, J=2.20 Hz,1H) 6.72 (d, J=7.03 Hz, 1H) 6.95 (d, J=8.35 Hz, 1H) 7.04 (m, 2H) 7.14(dd, J=9.23, 2.20 Hz, 1H) 7.30 (m, 3H) 7.39 (t, J=6.81 Hz, 1H) 7.83 (d,J=6.15 Hz, 1H) 8.05 (d, J=9.23 Hz, 1H) 8.53 (t, J=6.15 Hz, 1H). MS 543(M+H).

Example 242-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-(2-methoxy-5-sulfamoyl-benzyl)-acetamidetrifluoroacetic acid salt

24A 3-(Hydroxymethyl)-4-methoxybenzenesulfonamide

To a solution of methyl 2-methoxy-5-sulfamoylbenzoate (245 mg, 1.0 mmol)in THF (5.0 mL), LiBH₄ (2.0 M in THF, 1.0 mL) was added. After stirringat rt for 5.0 h, another portion of LiBH₄ (1.0 mL) was added followed by1.0 ml of MeOH. The mixture was stirred for 3 h, diluted with EtOAc andquenched with 5% citric acid. Extraction with EtOAc, drying with Na₂SO₄and evaporation of solvent gave 24A (240 mg) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 3.86 (s, 3H) 4.66 (d, J=6.15 Hz, 2H) 4.75 (s, 2H)6.88 (d, J=8.79 Hz, 1H) 7.80 (dd, J=8.79, 2.20 Hz, 1H) 7.85 (d, J=2.20Hz, 1H).

24B 3-(Azidomethyl)-4-methoxybenzenesulfonamide

To a solution of 24A (230 mg, 1.0 mmol) in THF (4.0 mL), DPPA (0.5 mL,2.0 eq) and DBU (0.34 mL, 2.0 eq) were added. The mixture was stirred atrt over night. It was diluted with EtOAc, quenched with 5% citric acid.The organic layer was washed with brine, dried with Na₂SO₄. The productwas purified by chromatography eluting with hexanes/EtOAc (1:1) to give120 mg of 24B as white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.90 (s, 3H)4.35 (s, 2H) 5.23 (s, 2H) 6.95 (d, J=8.35 Hz, 1H) 7.81 (d, J=2.20 Hz,1H) 7.87 (dd, J=8.79, 2.20 Hz, 1H).

24C 3-(Aminomethyl)-4-methoxybenzenesulfonamide

To a solution of 24B (116 mg) in MeOH (10 mL), Pd/C (10% by weight, 30mg) was added. This mixture was hydrogenated with a H₂ balloon for 4.0h. After filtration and concentration, 24C was obtained as a whitesolid. ¹H NMR (400 MHz, CD₃CN) δ ppm 3.75 (s, 2H) 3.86 (s, 3H) 7.00 (d,J=8.35 Hz, 1H) 7.70 (dd, J=8.57, 2.42 Hz, 1H) 7.81 (d, J=2.20 Hz, 1H).

24D

Example 24 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 24C. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.29(d, J=6.15 Hz, 6H) 1.36 (t, J=7.03 Hz, 3H) 3.74 (s, 3H) 3.99 (q, J=7.03Hz, 2H) 4.47 (m, 3H) 5.07 (s, 1H) 6.61 (d, J=2.20 Hz, 1H) 6.77 (d,J=7.03 Hz, 1H) 6.97 (t, J=8.13 Hz, 2H) 7.06 (m, 2H) 7.15 (dd, J=9.23,2.20 Hz, 1H) 7.30 (d, J=7.03 Hz, 1H) 7.75 (m, 2H) 8.06 (d, J=9.23 Hz,1H) 8.61 (t, J=5.93 Hz, 1H). LS-MS 594 (M+H).

Example 25N-(3-(Aminosulfonyl)aminobenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

25A Benzyl chlorosulfonylcarbamate

To a solution of chlorosulfonyl isocynate (5.0 mL, 57.4 mmol) in CH₂Cl₂(20 mL) at 0° C., benzyl alcohol (5.94 mL, 57.4 mmol) was added slowly.After completion of addition, the cooling bath was removed and stirredat rt for 30 min. Evaporation of the volatile and trituration withpetroleum ether gave 25A as white solid product.

25B [(3-Cyanophenylamino)sulfonyl] carbamic acid phenylmethyl ester

A mixture of 3-aminobenzonitrile (119 mg, 1.0 mmol), 25A (287 mg, 1.15mmol) and Et₃N (0.174 mL, 1.2 mmol) in CH₂Cl₂ (5.0 mL) was stirred at rtover night. It was diluted with EtOAc, washed with 1.0 N HCl, sat.NaHCO₃ and brine. After drying over Na₂SO₄ and evaporation of solvent,25B was obtained as a solid with sufficient purity for next step. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 5.05 (s, 2H) 7.20 (m, 2H) 7.29 (m, 3H) 7.41 (m,1H) 7.49 (m, 3H).

25C 3-(Aminosulfonyl)amino benzylamine

To a solution of 25B (200 mg) in MeOH (8 mL), Pd/C (10% by weight, 61mg) and 4.0 N HCl in dioxane (2.0 eq) were added. This mixture washydrogenated with a H₂ balloon for 4 h. After filtration andconcentration, the product 25C was obtained as HCl salt. ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.93 (d, J=5.71 Hz, 2H) 7.08 (d, J=8.35 Hz, 2H) 7.19(s, 2H) 7.28 (m, 2H) 8.47 (s, 3H) 9.69 (s, 1H).

25D

Example 25 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 25C. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.29(d, J=6.15 Hz, 6H) 1.36 (t, J=7.03 Hz, 3H) 3.99 (t, J=7.03 Hz, 2H) 4.37(d, J=4.39 Hz, 2H) 4.52 (m, 1H) 5.07 (s, 1H) 6.65 (d, J=2.20 Hz, 1H)6.82 (m, 2H) 6.96 (d, J=8.35 Hz, 1H) 7.11 (m, 6H) 7.31 (d, J=7.03 Hz,1H) 8.07 (d, J=9.23 Hz, 1H). LC-MS 579 (M+H).

Example 26(R)-N-(3-(Aminosulfonyl)aminobenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamide

Example 26 (30 mg) was separated from the racemic mixture (110 mg) ofExample 25 using a semi-preparative HPLC equipped with a Chiralpak® AD-Hcolumn (2 cm×25 m, 5μ). The separation was performed using an isocraticmethod of 40% ethanol/isopropanol (1:1) in heptane with 0.06%diethylamine and a flow rate of 12 mL/min. Retention time for Example 26was 28 min. Retention time for the other isomer (33 mg) was 18 min.LC-MS 579 (M+H).

Example 273-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenylsulfamate trifluoroacetic acid salt

27A Sulfamoyl chloride

Formic acid (1.0 mL, 26.5 mmol) was added dropwise to chlorosulfonylisocyanate (2.31 mL, 26.5 mmol) at 0° C. At the end of addition,stirring continued at rt for 3.0 h. Anhydrous toluene (20 mL) was added.The insoluble was filtered. The filtrate was condensed (<30° C.) to give27A as a slightly yellow solid.

27B 3-Cyanophenyl sulfamate

To a solution of 3-hydroxybenzonitrile (120 mg, 1.0 mmol) in DMA (2.0mL) at 0° C., 27A (232 mg, 2.0 mmol) was added. Cooling bath was removedand the reaction was stirred at rt for 2 h. It was diluted with EtOAc,washed with sat. NaHCO₃ and brine, dried with Na₂SO₄. After evaporationof solvent, 27B was obtained as viscous oil that was sufficient pure fornext step. ¹H NMR (400 MHz, CDCl₃) δ ppm 5.79 (s, 2H) 7.52 (m, 1H) 7.59(m, 2H) 7.64 (s, 1H).

27C 3-(Aminomethyl)phenyl sulfamate

To a solution of 27B (200 mg) in MeOH (8 mL), Pd/C (10% by weight, 50mg) and 4.0 N HCl in dioxane (2.0 eq) were added. This mixture washydrogenated with a H₂ balloon over night. After filtration andconcentration, 27C was obtained as HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δppm 4.03 (q, J=5.71 Hz, 2H) 6.29 (s, 3H) 7.28 (d, J=7.47 Hz, 1H) 7.46(m, 3H) 8.11 (s, 2H) 8.56 (s, 3H).

27D

Example 27 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 27C. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.29(d, J=6.15 Hz, 6H) 1.37 (t, J=7.03 Hz, 3H) 4.02 (q, J=7.03 Hz, 2H) 4.46(m, 3H) 5.08 (s, 1H) 6.67 (d, J=2.20 Hz, 1H) 6.82 (d, J=7.03 Hz, 1H)6.97 (d, J=7.91 Hz, 1H) 7.09 (m, 4H) 7.17 (m, 2H) 7.26 (t, J=7.91 Hz,1H) 7.32 (m, 1H) 8.08 (d, J=9.23 Hz, 1H) 8.89 (t, J=6.15 Hz, 1H). LC-MS580 (M+H).

Example 282-(1-Amino-isoquinolin-6-ylamino)-N-(3,5-bis-acetylamino-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

28A 3,5-Diaminobenzonitrile

A solution of 3,5-dinitrobenzonitrile (194 mg), Pd/C (10% by weight, 40mg) in EtOAc (8.0 mL) was hydrogenated with a H₂ balloon for 2.0 h atrt. After filtration and evaporation of solvent, 28A was obtained assufficient pure for next step. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.13 (s,1H), 6.32 (s, 2H).

28B N-(3-Acetylamino-5-cyano-phenyl)-acetamide

28A was stirred with acetic anhydride (0.57 mL, 6.0 eq) and pyridine(1.0 mL, 12 eq) in CH₂Cl₂ (2.0 mL) for 2.0 h. It was diluted with EtOAc,washed with 1.0 N HCl and brine. After drying over Na₂SO₄ andevaporation of solvent, 28B (110 mg) was obtained as solid. ¹H NMR (400MHz, CDCl₃) δ ppm 9.58 (s, 2H), 7.85 (s, 1H), 7.44 (s, 2H), 1.87 (s,6H).

28C N-(3-Acetylamino-5-aminomethyl-phenyl)-acetamide

To a solution of 28B (110 mg) in MeOH (8 mL), Pd/C (10% by weight, 80mg) and 4.0 N HCl in dioxane (0.25 mL, 2.0 eq) were added. This mixturewas hydrogenated with a H₂ balloon for 3.0 h. After filtration andconcentration, 28C, contaminated withN-(3-amino-5-aminomethyl-phenyl)-acetamide (ca 30%), was obtained as HClsalt.

28D

Example 28 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 28C. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.28(d, J=6.15 Hz, 6H) 1.35 (m, 3H) 2.07 (s, 6H) 3.97 (m, 3H) 4.27 (m, 1H)4.38 (m, 1H) 4.51 (m, 1H) 5.03 (s, 1H) 6.61 (d, J=1.76 Hz, 1H) 6.75 (d,J=7.03 Hz, 1H) 6.94 (m, 1H) 7.05 (m, 2H) 7.17 (m, 3H) 7.29 (d, J=7.47Hz, 1H) 7.68 (s, 1H) 8.05 (m, 1H) 8.83 (t, J=5.71 Hz, 1H). LS-MS 599(M+H).

Example 29N-(3-Acetylamino-5-amino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 29 was isolated as a minor product from Example 28 fromhydrolysis of one acetamide. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.28(d, J=6.15 Hz, 6H) 1.35 (t, J=7.03 Hz, 3H) 2.10 (s, 3H) 3.98 (m, 2H)4.42 (m, 2H) 5.06 (s, 1H) 6.62 (d, J=1.76 Hz, 1H) 6.77 (d, J=7.03 Hz,1H) 6.91 (s, 1H) 6.95 (d, J=8.35 Hz, 1H) 7.05 (m, 2H) 7.18 (dd, J=9.23,2.20 Hz, 1H) 7.24 (s, 1H) 7.30 (d, J=7.03 Hz, 1H) 7.69 (s, 1H) 8.08 (d,J=9.23 Hz, 1H) 8.94 (t, J=5.93 Hz, 1H). LC-MS 557(M+H).

Example 30N-(3-(Aminosulfonyl)aminobenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)acetamidetrifluoroacetic acid salt

Example 30 was prepared according to the general coupling-deprotectionusing Intermediate 4 and 25C. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 3.78(s, 3H) 3.81 (s, 3H) 4.36 (m, 2H) 5.09 (s, 1H) 6.65 (d, J=2.20 Hz, 1H)6.79 (d, J=7.03 Hz, 1H) 6.84 (d, J=7.91 Hz, 1H) 6.95 (d, J=9.23 Hz, 1H)7.11 (m, 6H) 7.30 (d, J=7.03 Hz, 1H) 8.06 (d, J=9.23 Hz, 1H) 8.82 (t,J=6.15 Hz, 1H). LC-MS 537 (M+H).

Example 31N-[3-(Acetyl-methyl-amino)-benzyl]-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 31 was prepared according to the general coupling-deprotectionusing Intermediate 2 and N-(3-(aminomethyl)phenyl)-N-methylacetamide. ¹HNMR (400 MHz, DMSO-d) δ ppm 1.23 (dd J=5.99, 1.83 Hz, 6H) 1.30 (t,J=6.97 Hz, 3H) 1.61 (s, 3H) 2.99 (s, 3H) 3.97 (q, J=7.09 Hz, 3H) 4.31(m, 2H) 4.47 (m, 1H) 5.16 (d, J=6.85 Hz, 1H) 6.67 (s, 1H) 6.78 (d,J=7.09 Hz, 1H) 6.91 (d, J=8.56 Hz, 1H) 6.98 (s, 1H) 7.02 (m, 1H) 7.12(m, 2H) 7.17 (d, J=2.20 Hz, 1H) 7.27 (m, 2H) 7.41 (m, 1H) 7.61 (d,J=6.85 Hz, 1H) 8.15 (d, J=9.29 Hz, 1H) 8.35 (s, 2H) 8.88 (t, J=5.99 Hz,1H) 12.20 (s, 1H). LC-MS 556 (M+H).

Example 325-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)isophthalamidetrifluoroacetic acid salt

32A Diethyl 5-(azidomethyl)isophthalate

To a solution of diethyl 5-(hydroxymethyl)isophthalate(1.0 g, 3.96 mmol)and diiphenylphosphoryl azide (1.30 g, 4.75 mmol) in toluene (10 mL) at0° C., 1,8-diazabicyclo[5.4.0]undec-7-ene (0.66 g, 4.35 mmol) was added.The reaction mixture was warmed to rt and stirred overnight. It was thenwashed with water and then 10% citric acid. The organic layer was driedover sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified by flash column chromatography (1:4 ethylacetate/hexanes) to yield 1.1 g of white crystalline 32A.

32B 5-(Azidomethyl)isophthalic acid

To a solution of 32A (0.5 g, 1.8 mmol) in THF (15 mL) and ethanol (2 mL)1N LiOH (9 mL) was added. The reaction mixture was stirred overnight atrt and then neutralized and acidified with 1N HCl to pH 3-4. The aqueouslayer was extracted with ethyl acetate and then the organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo to give0.33 g (89%) of white solid 32B.

32C 5-(Azidomethyl)isophthalamide

To a solution of 32B (0.3 g, 1.44 mmol) in DMF (5 mL) pyridine (0.23 mL,2.88 mmol) was added and followed by di-t-butyl dicarbonate (0.95 g,4.34 mmol) and ammonium bicarbonate 0.34 g, 4.34 mmol). The reaction wasstirred overnight at rt and then poured into cold water. The productprecipitated and filtered to give 0.19 g (97%) of white solid 32C.

32D 5-(Aminomethyl)isophthalamide

To a solution of 32C (0.05 g, 0.24 mmol) in methanol (30 mL), 10% Pd/C(20 mg) was added under nitrogen and then a balloon filled with hydrogengas was introduced. The reaction was stirred for 1 h at rt. The catalystwas filtered off and the solvent was removed to give 0.034 g (72%) ofwhite solid 32D. ¹H NMR (400 MHz, DMSO-d₆) (ppm 1.96 (s, 2H) 3.78 (s,2H) 7.39 (s, 2H) 7.95 (d, J=1.71 Hz, 4H) 8.17 (s, 1H).

32E

Example 32 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 32D. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (d,J=6.11 Hz, 6H) 1.29 (t, J=6.97 Hz, 3H) 3.94 (q, J=6.77 Hz, 2H) 4.26 (m,2H) 4.44 (m, 2H) 5.17 (d, J=7.09 Hz, 1H) 6.59 (m, 1H) 6.79 (d, J=7.34Hz, 1H) 6.90 (d, J=8.56 Hz, 1H) 6.99 (d, J=10.27 Hz, 1H) 7.10 (d, J=1.96Hz, 1H) 7.24 (m, 1H) 7.38 (m, 1H) 7.43 (s, 2H) 7.59 (d, J=7.34 Hz, 1H)7.91 (d, J=1.22 Hz, 2H) 7.93 (s, 2H) 8.13 (d, J=9.05 Hz, 1H) 8.21 (s,1H) 8.28 (s, 2H) 8.91 (t, J=5.99 Hz, 1H) 12.07 (s, 1H). LS-MS 571 (M+H).

Example 331-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenyl)-3-methylureatrifluoroacetic acid salt

Example 33 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 1-(3-(aminomethyl)phenyl)-3-methylurea. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.29 (t, J=6.97 Hz, 3H) 2.62 (d, J=4.40 Hz, 3H)3.96 (q, J=6.93 Hz, 2H) 4.21 (m, 2H) 4.45 (m, 1H) 5.15 (d, J=6.85 Hz,1H) 5.96 (q, J=4.40 Hz, 1H) 6.61 (s, 1H) 6.66 (d, J=7.34 Hz, 1H) 6.79(d, J=7.09 Hz, 1H) 6.92 (d, J=8.31 Hz, 1H) 7.00 (d, J=1.96 Hz, 1H) 7.06(t, J=7.70 Hz, 1H) 7.13 (d, J=1.96 Hz, 1H) 7.22 (d, J=9.54 Hz, 1H) 7.26(s, 1H) 7.31 (s, 1H) 7.40 (m, 1H) 7.58 (d, J=6.85 Hz, 1H) 8.15 (d,J=9.29 Hz, 1H) 8.32 (s, 2H) 8.44 (s, 1H) 8.80 (t, J=5.99 Hz, 1H) 12.14(d, J=3.18 Hz, 1H). LC-MS 557 (M+H).

Example 34 Methyl3-((2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenylcarbamatetrifluoroacetic acid salt

34A Methyl 3-cyanophenylcarbamate

To 3-aminobenzonitrile (1.0 g, 8.46 mmol) in CH₂Cl₂ and Et₃N (1.77 mL,12.7 mmol), methyl chloroformate (0.98 mL, 12.7 mmol) was added. Thereaction was stirred at rt overnight and then the solvent was evaporatedand dried under vacuo. The crude residue was purified by flash columnchromatography (1:1 ethyl acetate/hexanes) to give 34A (0.31 g, 21%yield).

34B methyl 3-(aminomethyl)phenylcarbamate

To 34A (0.31 g, 1.75 mmol) in methanol (30 mL) under nitrogen, 10% Pd/C(0.10 g) and conc. HCl (0.1 mL) were added and then a balloon filledwith hydrogen gas was introduced. The reaction was stirred for 3 h atrt. The catalyst was filtered off and the solvent was removed to give0.37 g of 34B as HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.65 (s, 3H)3.92 (q, J=5.79 Hz, 2H) 4.89 (m, 1H) 7.15 (d, J=7.58 Hz, 1H) 7.30 (t,J=7.95 Hz, 1H) 7.41 (d, J=8.31 Hz, 1H) 7.54 (s, 1H) 8.48 (s, 1H) 9.78(s, 1H).

34C

Example 34 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 34B. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (d,J=6.11 Hz, 6H) 1.29 (t, J=6.97 Hz, 3H) 3.63 (s, 3H) 3.96 (q, J=7.09 Hz,2H) 4.23 (m, 2H) 4.45 (m, 1H) 5.14 (d, J=6.85 Hz, 1H) 6.62 (s, 1H) 6.77(m, 2H) 6.91 (d, J=8.31 Hz, 1H) 7.01 (m, 1H) 7.13 (m, 2H) 7.26 (m, 2H)7.37 (s, 1H) 7.41 (m, J=6.85 Hz, 1H) 7.58 (d, J=7.09 Hz, 1H) 8.15 (d,J=9.29 Hz, 1H) 8.34 (d, J=6.85 Hz, 2H) 8.83 (t, J=5.87 Hz, 1H) 9.58 (s,1H) 12.21 (s, 1H). LC-MS 558 (M+H).

Example 35N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenyl)propionamidetrifluoroacetic acid salt

Example 35 was prepared according to the general coupling-deprotectionusing Intermediate 2 and N-(3-(aminomethyl)phenyl)propionamide. ¹H NMR(400 MHz, Methanol-d₄) δ ppm 1.17 (t, J=7.58 Hz, 3H) 1.29 (d, J=6.11 Hz,6H) 1.35 (t, J=6.97 Hz, 3H) 2.35 (q, J=7.74 Hz, 2H) 3.98 (m, 2H) 4.37(t, J=6.11 Hz, 2H) 4.52 (m, 1H) 5.05 (s, 1H) 6.64 (d, J=2.20 Hz, 1H)6.78 (d, J=7.09 Hz, 1H) 6.88 (d, J=7.58 Hz, 1H) 6.95 (d, J=8.07 Hz, 1H)7.07 (m, 2H) 7.16 (m, 2H).7.30 (d, J=7.09 Hz, 1H) 7.36 (d, J=8.56 Hz,1H) 7.46 (d, J=1.71 Hz, 1H) 8.07 (d, J=9.05 Hz, 1H) 8.79 (t, J=5.99 Hz,1H) 9.64 (s, 1H). LC-MS 556 (M+H).

Example 362-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-[1-(3-sulfamoyl-phenyl)-ethyl]-acetamidetrifluoroacetic acid salt

36A 3-tert-Butylsulfamoyl-N-methoxy-N-methyl-benzamide

To 3-(t-butylsulfonamide)benzoic acid (2.0 g, 7.8 mmol) in CH₂Cl₂ (50mL), HOAt (2.1 g, 15.5 mmol) and N-methoxymethanamine hydrochloride (1.3g, 13.6 mmol) were added, followed by N-methylmorpholine (2.5 mL, 23.2mmol) and EDC (2.97 g, 15.5 mmol). The reaction mixture was stirredovernight at rt and then washed with water and brine. The organic layerwas dried over Na₂SO₄ and solvent was evaporated. The crude residue waspurified by flash column chromatography to yield 36A (1.5 g, 64%) as awhite solid.

36B 3-Acetyl-N-tert-butylbenzenesulfonamide

To 36A (1.11 g, 3.69 mmol) in THF (20 mL) at −78° C., MeMgBr (3 M inether, 3.7 mL, 11.1 mmol) was added dropwise. The reaction mixture wasstirred at −78° C. for 20 min and then warmed to rt. Stirring wascontinued for 24 h at rt before saturated NH₄Cl was added at −78° C. Theproduct was extracted with ether and the organic layer was washed withwater, brine and dried over Na₂SO₄. The solvent was evaporated to yield36B (0.86 g, 90%) as a colorless semi-solid.

36C 3-(1-Aminoethyl)-N-tert-butylbenzenesulfonamide

To a solution of 36B (0.3 g, 1.17 mmol) in methanol (3 mL), a solutionof ammonium acetate (0.9 g, 11.7 mmol) and NaCNBH₃ (0.1 g, 1.64 mmol) inmethanol (4 mL) was added. The resulting reaction mixture was stirred atrt for 48 h. The reaction was acidified to pH 2 using 1 N HCl and thenthe solvent evaporated. The residue was redissolved in water and thenextracted with ether. The aqueous layer was basified to pH 10 usingsolid NaOH and then extracted with EtOAc. The organic extracts weredried over Na₂SO₄ and concentrated. Purification was performed by prepHPLC to give 36C (0.19 g) as a colorless semi-solid.

36D 3-(1-Aminoethyl)benzenesulfonamide

To 36C (0.12 g, 0.49 mmol), trifluoracetic acid (5 mL) was added andstirred at rt overnight. The reaction product was concentrated andplaced under vacuo for 1 h. The residue was dissolved in methanol and Abase resin (Supelco Diaion WA21J resin, 0.2 g) was added. The mixturewas stirred for 30 min and then filtered and concentrated to give 36D(0.08 g, 82%). ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.37 (d, J=6.60 Hz,3H) 4.28 (q, J=6.60 Hz, 1H) 5.64 (m, 2H) 7.32 (m, 2H) 7.55 (t, J=7.70Hz, 1H) 7.63 (m, 1H) 7.74 (m, 1H) 7.90 (t, J=1.71 Hz, 1H).

36E

Example 36 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 36D. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.28(m, 6H) 1.32 (m, 3H) 1.47 (m, 3H) 3.97 (m, 2H) 4.52 (m, 1H) 5.08 (m, 2H)6.60 (dd, J=20.17, 2.08 Hz, 1H) 6.78 (m, 1H) 6.95 (m, 1H) 7.14 (m, 5H)7.69 (m, 3H) 8.05 (t, J=9.29 Hz, 1H). LC-MS 578 (M+H).

Example 372-(1-Amino-isoquinolin-6-ylamino)-N-[1-(3-tert-butylsulfamoyl-phenyl)-ethyl]-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 37 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 36C. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.09(m, 9H) 1.29 (m, 6H) 1.38 (m, 3H) 1.44 (m, 3H) 4.00 (m, 2H) 4.52 (m, 1H)5.09 (m, 2H) 7.05 (m, 9H) 7.64 (m, 3H) 8.06 (t, J=9.66 Hz, 1H) 8.85 (dd,J=45.97, 7.58 Hz, 1H). LC-MS 634 (M+H).

Example 38N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenyl)butyramidetrifluoroacetic acid salt

38A N-(3-(Aminomethyl)phenyl)butyramide

38A was prepared by hydrogenation of N-(3-cyanophenyl)butyramide inMeOH/HCl with 10% Pd/C and a hydrogen balloon. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.90 (m, 3H) 1.59 (m, 2H) 2.27 (m, 2H) 3.89 (s, 2H) 7.12 (dd,J=7.95, 1.59 Hz, 1H) 7.29 (t, J=7.83 Hz, 1H) 7.49 (m, 1H) 7.73 (s, 1H)10.03 (s, 1H).

38B

Example 38 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 38A. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.89 (t,J=7.34 Hz, 3H) 1.22 (d, J=6.11 Hz, 6H) 1.29 (t, J=6.97 Hz, 3H) 1.58 (m,2H) 2.24 (t, J=7.34 Hz, 2H) 3.95 (q, J=6.85 Hz, 2H) 4.24 (m, 2H) 4.45(m, 1H) 5.15 (d, J=7.09 Hz, 1H) 6.62 (s, 1H) 6.79 (t, J=7.21 Hz, 3H)6.92 (d, J=8.31 Hz, 1H) 7.01 (m, 1H) 7.13 (m, 3H) 7.25 (d, J=11.00 Hz,1H) 7.40 (m, 3H) 7.54 (s, 1H) 7.58 (d, J=7.09 Hz, 1H) 8.15 (d, J=9.29Hz, 1H) 8.35 (s, 3H) 8.83 (t, J=5.87 Hz, 1H) 9.81 (s, 1H) 12.21 (s, 1H).LC-MS 570 (M+H).

Example 39N-(3-(Dimethylamino)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 39 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 3-dimethylaminobenzylamine. ¹H NMR (400 MHz,DMSO-d₆) (ppm 1.22 (d, J=5.87 Hz, 6H) 1.29 (t, J=6.97 Hz, 3H) 2.78 (m,6H) 3.96 (q, J=7.09 Hz, 2H) 4.23 (m, 2H) 4.46 (m, 1H) 5.16 (d, J=6.85Hz, 1H) 6.46 (d, J=7.34 Hz, 1H) 6.57 (d, J=9.29 Hz, 1H) 6.64 (s, 1H)6.77 (d, J=7.09 Hz, 1H) 6.92 (d, J=8.31 Hz, 1H) 7.03 (m, 2H) 7.16 (d,J=1.96 Hz, 1H) 7.25 (d, J=8.31 Hz, 1H) 7.41 (dd, J=6.60, 5.62 Hz, 1H)7.60 (d, J=7.09 Hz, 1H) 8.15 (d, J=9.05 Hz, 1H) 8.35 (s, 2H) 8.78 (t,J=5.75 Hz, 1H) 12.21 (s, 1H). LC-MS 528 (M+H).

Example 40N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenyl)cyclopropanecarboxamidebutyramide trifluoroacetic acid salt

40A N-(3-(Aminomethyl)phenyl)cyclopropanecarboxamide

40A was prepared by hydrogenation ofN-(3-cyanophenyl)cyclopropanecarboxamide in MeOH/HCl with 10% Pd/C and ahydrogen balloon. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78 (d, J=6.11 Hz,4H) 1.83 (m, 1H) 3.95 (d, J=5.62 Hz, 2H) 7.13 (d, J=7.83 Hz, 1H) 7.32(t, J=7.83 Hz, 1H) 7.49 (d, J=9.05 Hz, 1H) 7.78 (s, 1H) 8.29 (s, 2H)10.39 (s, 1H).

40B

Example 40 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 40A. ¹H NMR (400 MHz, DMSO-d₆) (ppm 0.77 (d,J=6.11 Hz, 4H) 1.22 (d, J=6.11 Hz, 6H) 1.29 (t, J=6.97 Hz, 3H) 1.75 (m,1H) 3.96 (q, J=7.09 Hz, 2H) 4.24 (m, 2H) 4.45 (m, 1H) 5.14 (d, J=6.85Hz, 1H) 6.62 (s, 1H) 6.79 (t, J=7.34 Hz, 2H) 6.91 (d, J=8.31 Hz, 1H)7.01 (m, 1H) 7.13 (m, 2H) 7.24 (d, J=8.31 Hz, 1H) 7.39 (d, J=7.09 Hz,2H) 7.54 (s, 1H) 7.58 (d, J=7.09 Hz, 1H) 8.15 (d, J=9.29 Hz, 1H) 8.35(s, 2H) 8.83 (t, J=5.75 Hz, 1H) 10.13 (s, 1H) 12.20 (s, 1H). LC-MS 568(M+H).

Example 411-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenyl)ureatrifluoroacetic acid salt

41A 1-(3-Cyanophenyl)urea

To 3-cyanophenyl isocyanate (1.0 g, 6.90 mmol) in THF (5 mL), ammoniumhydroxide (1.7 mL, 13.8 mmol) was added. The reaction was stirred for 2h at rt. The solvent was evaporated and the crude residue wasredissolved in ethyl acetate. The organic layer was washed with waterand brine and dried over sodium sulfate. The solvent was evaporated andthe crude residue was purified by flash column chromatography to 41A(0.37 g).

41B 1-(3-(Aminomethyl)phenyl)urea

To 41A (0.37 g, 2.29 mmol) in methanol (15 mL) under nitrogen, 10% Pd/C(45 mg) and conc HCl (0.1 mL) were added and then a balloon filled withhydrogen gas was introduced. The reaction was stirred overnight at rt.The catalyst was filtered off and the solvent was removed to give 41B(0.36 g, 78%) as HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.91 (q,J=5.79 Hz, 2H) 5.64 (s, 2H) 7.00 (d, J=7.58 Hz, 1H) 7.23 (t, J=7.83 Hz,1H) 7.37 (d, J=8.31 Hz, 1H) 7.51 (s, 1H) 8.33 (s, 2H) 8.96 (s, 1H).

41C

Example 41 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 41B. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22 (d,J=6.11 Hz, 6H) 1.30 (t, J=6.97 Hz, 3H) 3.96 (q, J=6.85 Hz, 2H) 4.22 (m,2H) 4.46 (m, 1H) 5.15 (d, J=7.58 Hz, 1H) 5.80 (s, 2H) 6.62 (s, 1H) 6.67(d, J=7.83 Hz, 1H) 6.80 (d, J=7.09 Hz, 1H) 6.92 (d, J=8.56 Hz, 1H) 7.00(m, 1H) 7.06 (t, J=7.83 Hz, 1H) 7.13 (d, J=1.96 Hz, 1H) 7.21 (d, J=8.07Hz, 1H) 7.25 (m, 1H) 7.32 (s, 1H) 7.41 (d, J=6.36 Hz, 1H) 7.58 (d,J=7.09 Hz, 1H) 8.15 (d, J=9.29 Hz, 1H) 8.30 (s, 2H) 8.46 (s, 1H) 8.80(t, J=5.87 Hz, 1H) 12.08 (s, 1H). LC-MS 543 (M+H).

Example 42N-(3-(Ethylamino)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

42A N-(3-Cyanophenyl)-2,2,2-trifluoroacetamide

To 3-aminobenzonitrile (1.0 g, 8.46 mmol) in CH₂Cl₂ (15 mL) and pyridine(1.86 mL, 23.0 mmol) at 0° C., trifluoroacetic anhydride (1.8 mL, 12.7mmol) was added. The reaction was allowed to warm to rt and stirred for24 h. The solvent was evaporated and the crude residue was redissolvedin ethyl acetate. The organic layer was washed with water and brine anddried over Na₂SO₄. The solvent was evaporated to give 42A (1.8 g) as anorange solid.

42B 3-(Ethylamino)benzonitrile

To 42A (0.50 g, 2.33 mmol) and K₂CO₃ (1.6 g, 11.65 mmol) in DMF (8 mL),ethyl iodide (0.37 mL, 4.66 mmol) was added. The reaction mixture wasstirred at 50° C. for 3 h. Methanol and water added to the reaction andstirred further 24 h. The reaction mixture was extracted with ethylacetate and washed with water and dried over Na₂SO₄. The solvent wasevaporated and the crude residue was purified by flash columnchromatography to give 42B (0.22 g, 65% yield) as a colorless oil.

42C 3-(Aminomethyl)-N-ethylbenzenamine

To 42B (0.22 g, 1.50 mmol) in methanol (8 mL) under nitrogen, 10% Pd/C(44 mg) and conc HCl (0.1 mL) were added and then a balloon filled withhydrogen gas was introduced. The reaction was stirred overnight at rt.The catalyst was filtered off and the solvent was removed to give 42C(0.246 g, 86%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14(t, J=7.09 Hz, 3H) 3.02 (dd, J=7.09, 5.38 Hz, 2H) 3.74 (s, 2H) 5.54 (t,J=5.50 Hz, 1H) 6.06 (m, 2H) 6.47 (dd, J=7.70, 1.83 Hz, 1H) 6.54 (m, 2H)7.03 (t, J=7.70 Hz, 1H).

42D

Example 42 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 42C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (m,9H) 1.36 (t, J=6.97 Hz, 3H) 3.28 (m, 2H) 4.48 (m, 3H) 5.11 (s, 2H) 6.68(d, J=2.20 Hz, 1H) 6.82 (d, J=6.85 Hz, 1H) 6.96 (d, J=8.31 Hz, 1H) 7.07(m, 1H) 7.12 (d, J=2.20 Hz, 1H) 7.19 (dd, J=9.17, 2.32 Hz, 1H) 7.28 (m,3H) 7.33 (d, J=7.09 Hz, 1H) 7.41 (t, J=7.95 Hz, 1H) 8.09 (d, J=9.29 Hz,1H) 8.98 (t, J=6.11 Hz, 1H). LC-MS 528 (M+H).

Example 43N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenyl)isobutyramidetrifluoroacetic acid salt

43A N-(3-(Aminomethyl)phenyl)isobutyramide

43A was prepared by hydrogenation of N-(3-cyanophenyl)isobutyramide inMeOH/HCl with 10% Pd/C and a hydrogen balloon. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.08 (d, J=6.85 Hz, 6H) 2.63 (m, 1H) 3.94 (s, 2H)7.15 (d, J=7.83 Hz, 1H) 7.32 (t, J=7.83 Hz, 1H) 7.51 (dd, J=8.07, 0.98Hz, 1H) 7.80 (s, 1H) 8.37 (s, 2H) 10.04 (s, 1H).

43B

Example 43 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 43A. ¹H NMR (400 MHz, Methanol-d₄) (ppm 1.17(d, J=7.03 Hz, 6H) 1.29 (d, J=6.15 Hz, 6H) 1.35 (t, J=7.03 Hz, 3H) 2.58(m, 1H) 3.98 (m, 2H) 4.37 (m, 2H) 4.52 (m, 1H) 5.06 (s, 1H) 6.64 (d,J=1.76 Hz, 1H) 6.78 (d, J=7.03 Hz, 1H) 6.89 (d, J=7.91 Hz, 1H) 6.95 (d,J=8.35 Hz, 1H) 7.06 (m, 2H) 7.16 (m, 2H) 7.30 (d, J=7.03 Hz, 1H) 7.38(d, J=7.47 Hz, 1H) 7.49 (s, 1H) 8.07 (d, J=9.23 Hz, 1H) 8.81 (t, J=5.93Hz, 1H) 9.63 (s, 1H). LC-MS 570 (M+H).

Example 44N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)phenyl)-3-methylbutanamidetrifluoroacetic acid salt

Example 44 was prepared according to the general coupling-deprotectionusing Intermediate 2 and N-(3-(aminomethyl)phenyl)-3-methylbutanamide.¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.35 (t, J=7.03 Hz, 3H) 2.15 (m, 3H)3.98 (m, 2H) 4.37 (m, 2H) 4.52 (m, 1H) 5.05 (s, 1H) 6.64 (d, J=1.76 Hz,1H) 6.78 (d, J=7.03 Hz, 1H) 6.89 (d, J=7.47 Hz, 1H) 6.95 (d, J=8.35 Hz,1H) 7.06 (m, 2H) 7.16 (m, 2H) 7.30 (d, J=7.03 Hz, 1H) 7.36 (d, J=7.91Hz, 1H) 7.49 (s, 1H) 8.07 (d, J=9.23 Hz, 1H) 8.81 (t, J=5.93 Hz, 1H)9.70 (s, 1H). LC-MS 584 (M+H).

Example 45N-(3-Formamidobenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

45A Benzyl 3-formamidobenzylcarbamate

To acetic anhydride (7.96 g, 78.0 mmol), formic acid (5.88 mL, 156 mmol)was added over 10 min at rt. Benzy 3-aminoobenzylcarbamate (1.0 g, 3.9mmol) in THF (10 mL) was then added to the reaction. The reaction wasstirred at rt for 24 h. The solvent was evaporated and the crude residuewas purified by flash column chromatography to yield 1.0 g of whitesolid 45A.

45B N-(3-(Aminomethyl)phenyl)formamide

To 45A (0.21 g, 0.74 mmol) in methanol (15 mL) under nitrogen, 10% Pd/C(40 mg) was added and then a balloon filled with hydrogen gas wasintroduced. The reaction was stirred for 30 min at rt. The catalyst wasfiltered off and the solvent was removed to give 0.11 g of white solid45B. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.86 (s, 2H) 3.68 (d, J=3.52Hz, 2H) 7.04 (d, J=7.47 Hz, 1H) 7.23 (t, J=7.69 Hz, 1H) 7.41 (m, 1H)7.51 (s, 1H) 8.24 (d, J=1.76 Hz, 1H) 10.12 (s, 1H).

45C

Example 45 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 45B. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.30(t, J=6.36 Hz, 6H) 1.36 (m, 3H) 3.99 (m, 2H) 4.37 (d, J=5.87 Hz, 2H)4.52 (m, 1H) 5.05 (s, 1H) 6.64 (d, J=2.20 Hz, 1H) 6.77 (m, 1H) 6.95 (m,2H) 7.07 (m, 2H) 7.17 (m, 2H) 7.31 (m, 1H) 7.37 (m, 1H) 7.48 (s, 1H)8.07 (m, 1H) 8.33 (m, 1H) 8.83 (m, 1H). LC-MS 528 (M+H).

Example 46N-(3-(Methylamino)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 46 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 3-methylaminobenzylamine. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.29 (d, J=6.11 Hz, 6H) 1.35 (t, J=6.97 Hz, 3H) 2.94(s, 3H) 4.00 (m, 2H) 4.47 (m, 3H) 5.10 (s, 1H) 6.68 (d, J=2.20 Hz, 1H)6.81 (d, J=7.09 Hz, 2H) 6.96 (d, J=8.31 Hz, 1H) 7.15 (m, 6H) 7.36 (m,2H) 8.08 (d, J=9.05 Hz, 1H) 8.95 (t, J=6.11 Hz, 1H). LC-MS 514 (M+H).

Example 47N-[1-(3-Acetylamino-phenyl)-ethyl]-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

47A N-(3-(1-Aminoethyl)phenyl)acetamide

To a solution of N-(3-acetylphenyl)acetamide (1.0 g, 5.6 mmol) inmethanol (10 mL), a solution of ammonium acetate (4.34 g, 56.4 mmol) andNaCNBH₃ (1.05 g, 16.8 mmol) in methanol (15 mL) was added. The resultingreaction mixture was stirred at rt for 48 h. The reaction was acidifiedto pH 2 using 1N HCl and then the solvent was evaporated. The residuewas redissolved in water and then extracted with ether. The aqueouslayer was basified to pH 10 using solid NaOH and then extracted withethyl acetate. The organic extract was washed with brine and dried oversodium sulfate and concentrated to give 47A. ¹H NMR (400 MHz,Methanol-d₄) (ppm 1.40 (d, J=6.85 Hz, 3H) 2.04 (s, 3H) 4.24 (q, J=6.85Hz, 1H) 6.85 (s, 2H) 7.11 (d, J=7.83 Hz, 1H) 7.31 (t, J=7.83 Hz, 1H)7.45 (d, J=8.07 Hz, 1H) 7.70 (s, 1H) 9.98 (s, 1H).

47B

Example 47 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 47A. ¹H NMR (400 MHz, Methanol-d₄) (ppm 1.28(d, J=6.11 Hz, 6H) 1.34 (m, 3H) 1.48 (d, J=7.09 Hz, 3H) 2.00 (d, J=58.44Hz, 3H) 3.94 (m, 2H) 4.51 (m, 1H) 5.01 (m, 1H) 5.08 (s, 1H) 6.64 (d,J=1.96 Hz, 1H) 6.76 (d, J=7.58 Hz, 1H) 6.80 (d, J=7.09 Hz, 1H) 6.93 (d,J=8.80 Hz, 1H) 7.04 (m, 3H) 7.16 (dd, J=9.17, 2.32 Hz, 1H) 7.27 (m, 1H)7.31 (d, J=7.09 Hz, 1H) 7.36 (s, 1H) 8.06 (d, J=9.29 Hz, 1H) 8.64 (d,J=8.07 Hz, 1H). LC-MS 556 (M+H).

Example 48 Diastereoisomer of Example 47N-[1-(3-Acetylamino-phenyl)-ethyl]-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 48, a diastereoisomer of Example 47, was separated by prep HPLC(YMC ODSS5 30×100 mm, 40 mL/min from 10% CH₃CN to 90% CH₃CN). Retentiontime for Example 47 is 7.5 min. and for Example 48 is 8.5 min. ¹H NMR(400 MHz, Methanol-d₄) δ ppm 1.29 (d, J=5.87 Hz, 6H) 1.37 (t, J=6.85 Hz,6H) 2.10 (s, 3H) 4.00 (m, 2H) 4.52 (m, 1H) 5.03 (d, J=13.45 Hz, 2H) 6.59(d, J=2.20 Hz, 1H) 6.72 (d, J=7.09 Hz, 1H) 6.95 (d, J=8.31 Hz, 1H) 7.10(m, 4H) 7.27 (m, 2H) 7.38 (m, 1H) 7.62 (s, 1H) 8.04 (d, J=9.29 Hz, 1H)8.74 (d, J=7.83 Hz, 1H).). LC-MS 556 (M+H).

Example 492-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N—((S)-1-phenylethyl)acetamidetrifluoroacetic acid salt

Example 49 was prepared according to the general coupling-deprotectionusing Intermediate 2 and (S)-1-phenylethanamine. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.27 (m, 12H) 3.98 (m, 2H) 4.53 (d, J=26.65 Hz, 1H)5.05 (m, 2H) 6.72 (m, 2H) 7.08 (m, 7H) 7.36 (m, 3H) 8.07 (t, J=8.56 Hz,1H) 8.68 (m, J=39.00, 7.95 Hz, 1H). LC-MS 499 (M+H).

Example 502-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N—((R)-1-phenylethyl)acetamidetrifluoroacetic acid salt

Example 50 was prepared according to the general coupling-deprotectionusing Intermediate 2 and (R)-1-phenylethanamine. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.36 (m, 12H) 3.97 (m, 2H) 4.53 (m, 1H) 5.04 (m, 3H)6.73 (m, 2H) 6.95 (dd, J=8.56, 4.89 Hz, 1H) 7.13 (m, 6H) 7.33 (m, 3H)8.07 (t, J=8.68 Hz, 1H) 8.68 (dd, J=39.13, 8.07 Hz, 1H). LC-MS 499(M+H).

Example 512-(1-Aminoisoquinolin-6-ylamino)-N-benzyl-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamidetrifluoroacetic acid salt

Example 51 was prepared according to the general coupling-deprotectionusing Intermediate 2 and N-methyl(phenyl)methanamine. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.29 (d, J=6.11 Hz, 6H) 1.35 (m, 3H) 3.00 (d, J=39.13Hz, 3H) 4.01 (m, 2H) 4.59 (m, 3H) 5.64 (d, J=10.03 Hz, 1H) 6.84 (m, 4H)7.09 (m, 2H) 7.17 (m, 2H) 7.27 (m, 4H) 8.04 (m, 1H). LC-MS 499 (M+H).

Example 52(R)-2-(1-aminoisoquinolin-6-ylamino)-N-benzyl-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamidetrifluoroacetic acid salt

Example 52 (34 mg) was separated from the racemic mixture (80 mg) ofExample 51 using a preparative HPLC equipped with a Chiralpak® AD column(5 cm×50 cm, 20μ). The separations were performed using an isocraticmethod of 95% 1:1 ethanol/methanol, 5% heptane with 0.1% diethylaminefor 120 min with a flow rate of 50 mL/min. Retention time for Example 52was 26 min. Retention time for the other isomer (32 mg) was 90 min. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.33 (m, 9H) 3.01 (m, 3H) 3.98 (m, 2H)4.59 (m, 3H) 5.61 (d, J=9.54 Hz, 1H) 6.70 (m, 2H) 7.05 (m, 6H) 7.25 (m,3H) 7.39 (dd, J=12.96, 6.60 Hz, 1H) 7.95 (m, 1H). LC-MS 499 (M+H).

Example 53N-(2-(Isopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)acetamidetrifluoroacetic acid salt

Example 53 was prepared according to the general coupling-deprotectionusing Intermediate 4 and Intermediate 14. ¹H NMR (400 MHz, Methanol-d₄)δ ppm 1.24 (m, 6H) 3.44 (m, 1H) 3.81 (d, J=17.61 Hz, 6H) 4.73 (m, 3H)5.10 (s, 1H) 6.64 (d, J=2.20 Hz, 1H) 6.80 (d, J=7.09 Hz, 1H) 6.97 (d,J=8.80 Hz, 1H) 7.09 (m, 2H) 7.18 (dd, J=9.17, 2.32 Hz, 1H) 7.35 (m, 2H)7.48 (m, 2H) 7.84 (dd, J=7.70, 1.59 Hz, 1H) 8.07 (d, J=9.29 Hz, 1H) 8.61(m, 1H). LC-MS 535 (M+H).

Example 54N-[1-(3-Acetylamino-phenyl)-ethyl]-2-(1-amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 54 was prepared according to the general coupling-deprotectionusing Intermediate 4 and 47A. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.48(d, J=6.85 Hz, 3H) 2.07 (s, 3H) 3.73 (s, 3H) 3.82 (s, 3H) 5.00 (m, 1H)5.09 (s, 1H) 6.64 (d, J=2.20 Hz, 1H) 6.79 (m, 2H) 6.93 (d, J=8.31 Hz,1H) 7.05 (m, 3H) 7.16 (dd, J=9.17, 2.32 Hz, 1H) 7.24 (m, 1H) 7.31 (m,2H) 8.06 (d, J=9.29 Hz, 1H) 8.65 (d, J=8.07 Hz, 1H). LC-MS 514 (M+H).

Example 55 Diastereoisomer of Example 54N-[1-(3-Acetylamino-phenyl)-ethyl]-2-(1-amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 55, a diastereoisomer of Example 54, was separated by prep HPLC(YMC ODSS5 30×100 mm, 40 mL/min from 5% CH₃CN to 42% CH₃CN). Retentiontime for Example 55 was 8.0 min and for Example 54 was 7.3 min. ¹H NMR(400 MHz, Methanol-d₄) δ ppm 1.38 (d, J=7.09 Hz, 3H) 2.11 (s, 3H) 3.81(s, 3H) 3.83 (s, 3H) 5.01 (m, 1H) 5.06 (s, 1H) 6.60 (d, J=1.96 Hz, 1H)6.73 (d, J=7.09 Hz, 1H) 6.97 (d, J=8.31 Hz, 1H) 7.13 (m, 4H) 7.28 (m,2H) 7.38 (m, 1H) 7.62 (d, J=1.96 Hz, 1H) 8.05 (d, J=9.29 Hz, 1H) 8.76(d, J=8.07 Hz, 1H). LC-MS 514 (M+H).

Example 563-(2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)-3-phenylpropanoicacid trifluoroacetic acid salt

Example 56 was prepared according to the general coupling-deprotectionusing Intermediate 2 and methyl 3-amino-3-phenylpropanoate followed byhydrolysis of the methyl ester as in procedure 5E. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.28 (m, 6H) 1.34 (t, J=6.97 Hz, 3H) 2.83 (m, 2H)3.94 (m, 2H) 4.52 (m, 1H) 5.06 (s, 1H) 5.38 (m, 1H) 6.66 (d, J=1.96 Hz,1H) 6.92 (m, 2H) 7.04 (m, 4H) 7.14 (m, 4H) 7.31 (d, J=7.09 Hz, 1H) 8.07(d, J=9.05 Hz, 1H) 8.81 (d, J=8.31 Hz, 1H). LC-MS 543 (M+H).

Example 57 (3R)-Methyl3-(2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)-3-phenylpropanoatetrifluoroacetic acid salt

Example 57 was prepared according to the general coupling-deprotectionusing Intermediate 2 and (R)-methyl 3-amino-3-phenylpropanoate. ¹H NMR(400 MHz, Methanol-d₄) δ ppm 1.05 (m, 3H) 1.29 (d, J=6.11 Hz, 6H) 1.35(m, 3H) 2.81 (m, 2H) 3.75 (m, J=7.21, 7.21 Hz, 1H) 4.00 (m, 3H) 4.51 (m,1H) 5.03 (d, J=11.98 Hz, 1H) 5.41 (s, 1H) 6.73 (m, 2H) 6.94 (d, J=8.07Hz, 1H) 7.11 (m, 5H) 7.32 (m, 4H) 8.06 (t, J=9.17 Hz, 1H). LC-MS 557(M+H).

Example 58(3R)-3-(2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)-3-phenylpropanoicacid trifluoroacetic acid salt

Example 58 was prepared by saponification of Example 57 as in procedure5E. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.26 (m, 6H) 1.33 (t, J=6.97 Hz,3H) 2.82 (m, 2H) 3.94 (d, J=0.98 Hz, 2H) 4.51 (m, 1H) 5.05 (s, 1H) 5.37(dd, J=8.80, 5.62 Hz, 1H) 6.66 (d, J=2.20 Hz, 1H) 6.91 (m, 2H) 7.03 (m,4H) 7.13 (m, 4H) 7.31 (d, J=7.09 Hz, 1H) 8.06 (d, J=9.29 Hz, 1H). LC-MS543 (M+H).

Example 59(3S)-3-(2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)-3-phenylpropanoicacid trifluoroacetic acid salt

Example 59 was prepared according to the general coupling-deprotectionusing Intermediate 2 and (S)-methyl 3-amino-3-phenylpropanoate followedby hydrolysis of the methyl ester as in procedure 5E. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.27 (m, 6H) 1.35 (m, 3H) 2.76 (m, 2H) 3.99 (m, 2H)4.50 (dd, J=12.10, 5.99 Hz, 1H) 5.06 (s, 1H) 5.38 (m, 1H) 6.60 (s, 1H)6.74 (d, J=7.09 Hz, 1H) 6.94 (d, J=8.07 Hz, 1H) 7.03 (m, 2H) 7.14 (dd,J=9.17, 2.08 Hz, 1H) 7.32 (m, 6H) 8.05 (d, J=9.29 Hz, 1H) 8.91 (m,J=8.31 Hz, 1H). LC-MS 543 (M+H).

Example 60 (3R)-Ethyl3-(3-acetamidophenyl)-3-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)propanoatetrifluoroacetic acid salt

60A (R)-Ethyl3-(benzyl((S)-1-phenylethyl)amino)-3-(3-nitrophenyl)propanoate

To a solution of (S)-N-benzyl-α-methyl-benzylamine (1.52 g, 7.2 mmol)inTHF (20 mL), n-BuLi in hexanes (4.5 mL, 1.6 M) was added dropwise at−78° C. The reaction mixture was stirred for 30 min. at −78° C. To thesolution was added ethyl-m-nitrocinnamate (1.0 g, 4.52 mmol) in THF (15mL). After stirring for 30 min at −78° C., saturated NH₄Cl was added andthen the reaction product was extracted with ethyl acetate. The organicextracts were washed with brine and dried over Na₂SO₄. The solvent wasevaporated and crude residue was purified by flash column chromatographyto give 60A (1.26 g, 65%) as a yellow oil.

60B (R)-Ethyl-3-amino-3-(3-aminophenyl)propanoate

To 60A (0.62 g, 1.42 mmol) in methanol (10 mL), water (0.075 mL) andacetic acid (0.0375 mL) under nitrogen, 20% Pd(OH)₂/C (0.15 g) was addedand then a balloon filled with hydrogen gas was introduced. The reactionwas stirred for 2 h at rt. The catalyst was filtered off and the solventevaporated. The crude residue was purified by flash columnchromatography to give 60B (0.27 g).

60C (R)-3-(3-Amino-phenyl)-3-tert-butoxycarbonylamino-propionic acidethyl ester

To 60B (0.058 g, 0.28 mmol) in methanol (4 mL), di-t-butyl dicarbonateEt₃N (0.077 mL, 0.55 mmol) was added. The reaction was stirred at rt for45 min. The solvent was evaporated and the crude residue was purified byflash column chromatography to give 0.59 g (69%) of 60C. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.18 (t, J=7.21 Hz, 3H) 1.40 (s, 9H) 2.71 (m,2H) 4.08 (m, 2H) 4.93 (m, J=6.85 Hz, 1H) 6.60 (m, 2H) 6.66 (s, 1H) 7.03(t, J=7.83 Hz, 1H) 7.09 (d, J=7.83 Hz, 1H).

60D (R)-3-(3-Acetylamino-phenyl)-3-tert-butoxycarbonylamino-propionicacid ethyl ester

To 60C, acetic anhydride (0.3 mL) was added. The reaction was stirred atroom temp for 20 min. The solvent was removed and placed under highvacuo for 24 h to give 60D (0.056 g, 85%) as a white solid.

60E (R)-3-(3-Acetylamino-phenyl)-3-amino-propionic acid ethyl ester

To 60D (0.056 g, 0.16 mmol), 4 N HCl in dioxane (2.5 mL), was added. Thereaction was stirred for 2 h at rt. The solvent was removed and driedover high vacuo to give 60E (0.043 g) as the HCl salt. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.21 (t, J=7.09 Hz, 3H) 2.14 (s, 3H) 3.02 (m, 2H)3.66 (m, 2H) 4.15 (q, J=7.09 Hz, 2H) 4.68 (t, J=7.21 Hz, 1H) 7.18 (m,1H) 7.40 (m, 2H) 7.86 (s, 1H).

60F

Example 60 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 60E. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.06(m, 3H) 1.32 (m, 9H) 2.09 (m, 3H) 2.84 (m, 2H) 3.94 (m, 4H) 4.49 (dd,J=12.23, 6.11 Hz, 1H) 5.02 (d, J=1.96 Hz, 1H) 5.37 (m, 1H) 6.57 (d,J=18.34 Hz, 1H) 6.84 (m, 3H) 7.04 (m, 3H) 7.12 (m, 1H) 7.40 (m, 3H) 8.03(t, J=8.80 Hz, 1H) 8.88 (m, 1H). LC-MS 826 (M+H).

Example 61(3R)-3-(3-Acetamidophenyl)-3-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)propanoicacid trifluoroacetic acid salt

Example 61 was prepared by saponification of Example 60 as in procedure5E. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.33 (m, 9H) 2.08 (m, 3H) 2.83(m, 2H) 3.94 (m, 2H) 4.50 (m, 1H) 5.04 (m, 1H) 5.36 (dd, J=9.29, 4.65Hz, 1H) 6.58 (d, J=12.72 Hz, 1H) 6.83 (m, 3H) 7.08 (m, 4H) 7.35 (m, 3H)8.03 (m, 1H) 8.87 (m, 1H). LC-MS 600 (M+H).

Example 622-(1-Amino-isoquinolin-6-ylamino)-2-(4-chloro-3-ethoxy-phenyl)-N-(3-methanesulfonylamino-benzyl)-acetamidetrifluoroacetic acid salt

Example 62 was prepared according to the general coupling-deprotectionusing Intermediate 15 and commercial N-(3-(aminomethyl)phenyl)acetamideHCl salt. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.38 (t, J=7.03 Hz, 3H)2.09 (s, 3H) 4.02 (q, J=6.88 Hz, 2H) 4.37 (d, J=5.71 Hz, 2H) 5.13 (s,1H) 6.65 (d, J=2.20 Hz, 1H) 6.79 (d, J=7.03 Hz, 1H) 6.90 (d, J=7.91 Hz,1H) 7.08 (dd, J=8.35, 1.76 Hz, 1H) 7.14-7.20 (m, 3H) 7.31 (d, J=7.03 Hz,2H) 7.33-7.37 (m, 2H) 7.44 (s, 1H) 8.08 (d, J=9.23 Hz, 1H) 8.87 (b, 1H);LC MS (518 (M+H).

Example 63N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(4-chloro-3-ethoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 63 was prepared according to the general coupling-deprotectionusing Intermediate 15 and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄)δ ppm 1.16 (t, J=7.25 Hz, 3H) 1.35-1.40 (m, 3H) 2.13 (s, 3H) 3.22-3.28(m, 2H) 3.96-4.05 (m, 2H) 4.60-4.66 (m, 1H) 4.71-4.77 (m, 1H) 5.17 (s,1H) 6.62 (d, J=2.20 Hz, 1H) 6.77 (d, J=7.03 Hz, 1H) 7.07 (dd, J=8.13,1.98 Hz, 1H) 7.11 (d, J=1.76 Hz, 1H) 7.17 (dd, J=9.23, 2.20 Hz, 1H)7.29-7.32 (m, 1H) 7.34 (d, J=7.91 Hz, 1H) 7.58 (dd, J=8.35, 2.20 Hz, 1H)7.74 (d, J=1.76 Hz, 1H) 7.77 (d, J=8.79 Hz, 1H) 8.06 (d, J=9.23 Hz, 1H)8.68 (t, J=6.15 Hz, 1H); LC MS (610 (M+H).

Example 64N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-fluoro-phenyl)-acetamidetrifluoroacetic acid salt

64A 5-Bromo-2-fluorophenol

To a solution of 2,2,6,6-tetramethyl piperidine (5.6 mL, 33.2 mmol) inTHF at −20° C. was added n-BuLi (1.6 M in hexanes, 18.8 mL, 30 mmol).The mixture was stirred at −20° C. for 10 min before it was cooled to−78° C. 1-Bromo-4-fluorobenzene (2.95 mL, 27 mmol) was added over 10 minand the mixture was stirred at −78° C. for 2.0 h before trimethyl borate(6.0 mL, 54 mmol) was added. The mixture was stirred at −78° C. for 30min and then at rt for 2.0 h. After it was cooled back to 0° C., glacialacetic acid (4.86 mL, 81 mmol) was added and stirred for 30 min,followed by addition of 30% H₂O₂ (4.86 mL, 81 mmol). The mixture wasstirred at rt for 24 h., quenched by addition of MnO₂ (40 mg). Afterstirring at rt for 30 min., the cloudy solution was filtered through apad of wet Celite® and extracted with EtOAc. The EtOAc layer was washedwith aquous NaHSO₃, brine and dried over Na₂SO₄. The crude residue waspurified by flash column chromatography (EtOAc:hexanes=1:5) to give 4.4g (85%) of 64A as a liquid. ¹H NMR (400 MHz, CDCl₃) δ ppm 5.39 (s, 1H)6.90-6.98 (m, 2H) 7.14 (dd, J=8.13, 1.98 Hz, 1H).

64B 4-Bromo-2-ethoxy-1-fluorobenzene

To a solution of 64A (4.4 g, 23 mmol) and K₂CO₃ (6.4 g, 46 mmol) in DMF(30 mL) was added ethyl iodide (2.49 mL, 31 mmol) at rt. The mixture washeated at 50° C. for 2.0 h. After cooled to rt, it was diluted withether, washed with water and brine, dried over MgSO₄. The crude residuewas purified by flash column chromatography (EtOAc:hexanes=1:5) to give3.86 g (77%) of 64B as viscous oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.47(m, 3H) 4.00 (m, 2H) 6.96-7.08 (m, 3H).

64C 3-Ethoxy-4-fluorophenylboronic acid

To a solution of 64B (3.86 g, 17.6 mmol) in THF (60 mL) at −78° C. wasadded n-BuLi (1.6 M in hexanes, 14.3 mL, 22.8 mmol). The mixture wasstirred at −78° C. for 40 min before trimethyl borate (3.63 mL, 33 mmol)was added. The reaction was left stirring from −78° C. to rt over 4 h.It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washedwith brine and dried over Na₂SO₄. After evaporation of the solvent, thecrude solid product was triturated with EtOAc/hexanes (1:4). Afterfiltration, 64C (2.2 g, 69% yield) was collected as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.42 (t, J=7.03 Hz, 3H) 4.11 (q, J=7.03 Hz,2H) 7.03 (dd, J=11.42, 8.35 Hz, 1H) 7.18-7.29 (m, 2H) 7.35 (d, J=7.91Hz, 1H).

64D2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-fluorophenyl)aceticacid

A mixture of 64C (43 mg, 0.23 mmol), Intermediate 1 (72 mg, 0.2 mmol)and glyoxylic acid monohydrate (21 mg, 0.23 mmol) in 1,2-dichloroethane(0.8 mL) was heated at 100° C. for 5 min. in a Microwave Reactor. Thecrude product was purified by flash column chromatography(CH₂Cl₂:MeOH=100:15) to give 36 mg (32%) of 64D as a solid. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.26 (s, 18H) 4.08 (dd, J=12.30, 7.03 Hz, 2H)4.98 (s, 1H) 6.61 (d, J=2.20 Hz, 1H) 7.03 (s, 1H) 7.13 (s, 1H) 7.25 (s,2H) 7.38 (d, J=6.15 Hz, 1H) 7.61 (d, J=9.23 Hz, 1H) 7.99 (d, J=6.15 Hz,1H); LC MS 556 (M+H).

64E

Example 64 was prepared according to the general coupling-deprotectionusing 64D and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.36 (t, J=7.03 Hz, 3H) 2.08 (s, 3H)4.01 (q, J=7.03 Hz, 2H) 4.36 (d, J=5.71 Hz, 2H) 5.11 (s, 1H) 6.63 (d,J=2.20 Hz, 1H) 6.76 (d, J=7.03 Hz, 1H) 6.90 (d, J=7.91 Hz, 1H) 7.08 (d,J=8.35 Hz, 2H) 7.13-7.22 (m, 3H) 7.28-7.35 (m, 2H) 7.43 (s, 1H) 8.07 (d,J=9.23 Hz, 1H) 8.87 (t, J=5.93 Hz, 1H); LC MS 502 (M+H).

Example 65N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-fluoro-phenyl)-acetamidetrifluoroacetic acid salt

Example 65 was prepared according to the general coupling-deprotectionusing 64D and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.16(t, J=7.25 Hz, 3H) 1.35 (t, J=7.03 Hz, 3H) 2.12 (s, 3H) 3.22-3.29 (m,2H) 3.95-4.05 (m, 2H) 4.60-4.66 (m, 1H) 4.71-4.77 (m, 1H) 5.15 (s, 1H)6.60 (d, J=2.20 Hz, 1H) 6.75 (d, J=7.03 Hz, 1H) 7.07 (d, J=7.91 Hz, 2H)7.15 (d, J=9.23 Hz, 2H) 7.29 (d, J=7.03 Hz, 1H) 7.58 (dd, J=8.57, 1.98Hz, 1H) 7.71 (d, J=2.20 Hz, 1H) 7.76 (d, J=8.79 Hz, 1H) 8.05 (d, J=9.23Hz, 1H) 8.67 (t, J=5.93 Hz, 1H); LC MS 594 (M+H).

Example 662-(1-Amino-isoquinolin-6-ylamino)-N-(2-cyclopropanesulfonyl-benzyl)-2-(3-ethoxy-4-fluoro-phenyl)-acetamidetrifluoroacetic acid salt

Example 66 was prepared according to the general coupling-deprotectionusing 64D and Intermediate 7. ¹H NMR (400 MHz, Methanol-d₄) δ ppm0.96-1.04 (m, 2H) 1.10-1.22 (m, 2H) 1.36 (t, J=7.03 Hz, 3H) 2.80-2.86(m, 1H) 4.03 (qd, J=7.10, 4.61 Hz, 2H) 4.80 (d, J=5.71 Hz, 1H) 5.18 (s,1H) 6.65 (d, J=2.20 Hz, 1H) 6.79 (d, J=7.03 Hz, 1H) 7.07-7.12 (m, 2H)7.15-7.23 (m, 2H) 7.32 (d, J=7.03 Hz, 1H) 7.37 (d, J=7.47 Hz, 1H)7.41-7.51 (m, 2H) 7.80-7.83 (m, 1H) 8.07 (d, J=9.23 Hz, 1H) 8.70 (t,J=5.93 Hz, 1H); LC MS 549 (M+H).

Example 67N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2,5-dimethoxy-phenyl)-acetamidetrifluoroacetic acid salt

67A2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(2,5-dimethoxyphenyl)aceticacid

A mixture of 2,5-dimethoxyphenylboronic acid (29 mg, 0.16 mmol),Intermediate 1 (50 mg, 014 mmol) and glyoxylic acid monohydrate (15 mg,0.16 mmol) in 1,2-dichloroethane (0.7 mL) was heated at 100° C. for 5min in a Microwave Reactor. The crude product was purified by flashcolumn chromatography (CH₂Cl₂:MeOH=100:15) to give 26 mg (33%) of 67A asa solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.26 (s, 18H) 3.66 (s, 3H)3.92 (s, 3H) 5.44 (s, 1H) 6.70 (d, J=1.76 Hz, 1H) 6.78 (dd, J=9.01, 2.86Hz, 1H) 6.95 (d, J=9.23 Hz, 1H) 7.06 (d, J=2.64 Hz, 1H) 7.17 (dd,J=9.23, 2.20 Hz, 1H) 7.35 (d, J=5.71 Hz, 1H) 7.56 (d, J=9.23 Hz, 1H)7.98 (d, J=6.15 Hz, 1H); LC MS 554 (M+H).

67B

Example 67 was prepared according to the general coupling-deprotectionusing 67A and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 2.08 (s, 3H) 3.66 (s, 3H) 3.82 (s, 3H)4.32-4.43 (m, 2H) 5.55 (s, 1H) 6.64 (d, J=1.76 Hz, 1H) 6.77 (d, J=7.03Hz, 1H) 6.85-6.89 (m, 1H) 6.90 (d, J=7.91 Hz, 1H) 6.95-7.00 (m, 2H)7.12-7.19 (m, 2H) 7.28 (d, J=7.03 Hz, 1H) 7.34 (d, J=8.35 Hz, 1H) 7.43(s, 1H) 8.04 (d, J=9.23 Hz, 1H); LC MS 500 (M+H).

Example 68N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2,5-dimethoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 68 was prepared according to the general coupling-deprotectionusing 67A and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.17(t, J=7.47 Hz, 3H) 2.12 (s, 3H) 3.24 (q, J=7.18 Hz, 2H) 3.62-3.66 (s,3H) 3.82-3.86 (s, 3H) 4.67 (dd, J=6.15, 3.52 Hz, 2H) 5.52 (s, 1H) 6.57(d, J=2.20 Hz, 1H) 6.73 (d, J=7.03 Hz, 1H) 6.85 (td, J=8.57, 3.08 Hz,2H) 6.95 (d, J=8.79 Hz, 1H) 7.12 (dd, J=9.23, 2.64 Hz, 1H) 7.27 (d,J=7.03 Hz, 1H) 7.64-7.69 (m, 1H) 7.72-7.80 (m, 2H) 8.02 (d, J=9.23 Hz,1H) 8.25 (t, J=6.37 Hz, 1H); LC MS 592 (M+H).

Example 69N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(4-fluoro-3-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

69A 4-Bromo-2-methoxy-1-fluorobenzene

To a solution of 64A (3.3 g, 17.3 mmol) and K₂CO₃ (4.78 g, 34.6 mmol) inDMF (20 mL) was added methyl iodide (1.46 mL, 23.4 mmol) at rt. Themixture was heated at 40° C. for 2.0 h. After cooled to rt, it wasdiluted with ether, washed with water and brine, dried over MgSO₄. Thecrude residue was purified by flash column chromatography(EtOAc:hexanes=1:6) to give 2.74 g (77%) of 69A as viscous oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 3.89 (s, 3H), 6.95-7.00 (m, 3H).

69B 3-Methoxy-4-fluorophenylboronic acid

To a solution of 69A (2.7 g, 13.1 mmol) in THF (25 mL) at −78° C. wasadded n-BuLi (1.6 M in hexanes, 11.0 mL, 17.7 mmol). The mixture wasstirred at −78° C. for 40 min before trimethyl borate (2.7 mL, 24.3mmol) was added. The reaction was left stirring from −78° C. to rt over18 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc,washed with brine and dried over Na₂SO₄. After evaporation of thesolvent, the crude solid product was triturated with EtOAc/hexanes(1:4). After filtration, 69B (0.75 g, 35% yield) was collected as awhite solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 3.86 (s, 3H) 7.03-7.45(m, 3H).

69C2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-fluoro-3-methoxyphenyl)aceticacid

A mixture of 69B (39 mg, 0.23 mmol), Intermediate 1 (72 mg, 0.2 mmol)and glyoxylic acid monohydrate (21 mg, 0.23 mmol) in 1,2-dichloroethane(0.8 mL) was heated at 85° C. for 8 min in a Microwave Reactor. Thecrude product was purified by flash column chromatography(CH₂Cl₂:MeOH=100:15) to give 54 mg (50%) of 69C as a solid. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.27 (s, 18H) 3.83 (s, 3H) 4.97 (s, 1H) 6.61 (d,J=2.20 Hz, 1H) 7.00 (dd, J=10.99, 8.35 Hz, 1H) 7.12 (ddd, J=8.24, 4.28,1.98 Hz, 1H) 7.23 (dd, J=9.23, 2.20 Hz, 1H) 7.32 (dd, J=8.35, 2.20 Hz,1H) 7.38 (d, J=5.71 Hz, 1H) 7.61 (d, J=9.23 Hz, 1H) 7.99 (d, J=6.15 Hz,1H); LC MS 542 (M+H).

69D

Example 69 was prepared according to the general coupling-deprotectionusing 69C and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 6 ppm 2.08 (s, 3H) 3.81 (s, 3H)4.34-4.39 (m, 2H) 5.12 (s, 1H) 6.64 (d, J=2.20 Hz, 1H) 6.77 (d, J=7.03Hz, 1H) 6.90 (d, J=7.47 Hz, 1H) 7.08-7.19 (m, 4H) 7.24 (d, J=8.79 Hz,1H) 7.28-7.34 (m, 2H) 7.42 (s, 1H) 8.07 (d, J=9.23 Hz, 1H) 8.9 (br, 1H)LS MS 488 (M+H).

Example 70N-(5-Amino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(4-fluoro-3-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 70 was prepared according to the general coupling-deprotectionusing 69C and Intermediate 9. The acetamide was hydrolyzed to theaniline during the deprotection step. ¹H NMR (400 MHz, Methanol-d₄) δppm 1.13 (t, J=7.47 Hz, 3H) 3.11 (q, J=7.47 Hz, 2H) 3.81 (s, 3H) 4.56(d, J=5.71 Hz, 2H) 5.14 (s, 1H) 6.55-6.58 (m, 1H) 6.58-6.64 (m, 3H) 6.81(d, J=7.03 Hz, 1H) 7.05-7.12 (m, 3H) 7.15-7.19 (m, 2H) 7.20 (d, J=2.20Hz, 1H) 7.31 (d, J=7.03 Hz, 1H) 7.48 (d, J=8.35 Hz, 1H) 8.07 (d, J=9.23Hz, 1H) 8.48 (s, 1H). LS-MS 538 (M+H).

Example 71N-(3-Acetylamino-benzyl)-2-(4-aminomethyl-phenylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

71A2-(4-((tert-Butoxycarbonyl)methyl)phenylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid

A solution of Intermediate 2E (112 mg, 0.5 mmol), tert-butyl4-aminobenzylcarbamate (111 mg, 0.5 mmol) and glyoxylic acid monohydrate(46.1 mg, 0.5 mmol) in toluene (4.0 mL) was heated at 55° C. for 15 min.and then at rt for 18 h. Solvent was removed and the crude was purifiedby column chromatography (CH₂Cl₂:MeOH=25:1) to give 173 mg (74%) of 71Aas a solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.27 (d, J=6.15 Hz, 6H)1.35 (t, J=7.03 Hz, 3H) 1.42 (s, 9H) 4.01 (d, J=1.76 Hz, 1H) 4.03 (d,J=4.39 Hz, 3H) 4.43-4.49 (m, 1H) 6.57 (d, J=8.35 Hz, 2H) 6.87 (d, J=8.35Hz, 1H) 6.98 (d, J=8.79 Hz, 2H) 7.02 (dd, J=8.35, 2.20 Hz, 1H) 7.11 (d,J=1.76 Hz, 1H) LC MS 500 (M+H).

71B

Example 71 was prepared according to the general coupling-deprotectionusing 71A and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.29 (s, 6H) 1.36 (s, 3H) 2.12 (s, 3H)3.91-3.97 (m, 1H) 3.99-4.04 (m, 1H) 4.14 (s, 2H) 4.29-4.38 (m, 2H)4.52-4.59 (m, 1H) 5.28 (s, 1H) 6.84 (d, J=7.47 Hz, 1H) 6.91-7.01 (m, 2H)7.09 (s, 1H) 7.15 (t, J=7.91 Hz, 1H) 7.35 (d, J=7.91 Hz, 1H) 7.40-7.48(m, 3H) 7.56 (d, J=8.35 Hz, 2H); LC MS 488 (M−NH₃).

Example 722-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-[3-(propane-2-sulfonyl)-pyridin-2-ylmethyl]-acetamidetrifluoroacetic acid salt

72A 3-Fluoro-pyridin-1-ol

To a solution of 3-fluoropyridine (4.7 g, 48.4 mmol) in CH₂Cl₂ and 30%H₂O₂ (10 mL, 104 mmol) at rt was added methyl trioxorhenium (25 mg, 0.1mmol). The mixture was stirred at rt for 20 h before manganese dioxide(25 mg) was added and stirred for an additional 1.0 h. It was extractedwith CH₂Cl₂ (5×100 mL), dried over Na₂SO₄. After evaporation of solvent,72A (4.5 g, 90%) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.29-7.40 (m, 1H) 7.40-7.54 (m, 1H) 8.08-8.21 (m, 1H)8.46-8.56 (m, 1H).

72B 3-Fluoropicolinonitrile

To 72A (4.4 g, 39 mmol) in CH₂Cl₂ (150 mL) was added trimethylsilylcyanide (8.3 mL, 62 mmol). The mixture was heated at reflux for 6 h.Additional trimethylsilyl cyanide (16 mL) was added and refluxed foradditional 10 h. After cooled to rt, the reaction was quenched byaddition of 100 mL of sat. NaHCO₃. The organic layer was collected anddried over Na₂SO₄. The crude product was purified by columnchromatography (EtOAc:hexanes=6:9) to give 72B (2.5 g) as a solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.57 (m, 1H), 7.61 (m, 2H).

72C 3-(Isopropylthio)picolinonitrile

To a solution of 72B (246 mg, 2.0 mmol) in DMF (5.0 mL) was added K₂CO₃(484 mg, 3.5 mmol) and propane-2-thiol (0.33 mL, 3.5 mmol). The reactionwas heated at 40° C. for 18 h. The mixture was diluted with EtOAc,washed with water and brine, dried over Na₂SO₄. After evaporation ofsolvent, 72C (300 mg) was obtained as viscous oil. It was used for nextstep without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.36(d, J=6.59 Hz, 6H) 3.45-3.70 (m, 1H) 7.43 (dd, J=8.13, 4.61 Hz, 1H)8.42-8.66 (m, 1H).

72D (3-(Isopropylthio)pyridin-2-yl)methanamine HCl salt

To 72C (250 mg, 1.4 mmol) in MeOH (8.0 mL) was added 4.0 N HCl indioxane (1.0 mL) and 10% Pd/C (125 mg). The mixture was hydrogenated at60 psi for 18 h. After filtration and evaporation of solvent, 72D (310mg) was obtained as HCl salt. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.34(d, J=6.59 Hz, 6H) 3.53-3.63 (m, 1H) 4.40 (s, 2H) 7.50 (dd, J=7.91, 4.83Hz, 1H) 8.06 (d, J=7.91 Hz, 1H) 8.53 (d, J=4.83 Hz, 1H).

72E tert-Butyl (3-(isopropylthio)pyridin-2-yl)methylcarbamate

To a solution of 72D (100 mg, 0.39 mmol) in MeOH (2.0 mL) was addeddi-tert-butyl dicarbonate (1.0 M in CH₂Cl₂, 0.49 mL, 0.49 mmol). Themixture was stirred at rt for 6 h. After removal of solvent, 72E (300mg) was obtained. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.28 (d, J=6.59 Hz, 6H)1.46 (s, 9H) 3.35 (dt, J=13.18, 6.59 Hz, 1H) 4.56 (d, J=3.95 Hz, 2H)6.10 (s, 1H) 7.16 (dd, J=7.47, 4.83 Hz, 1H) 7.68 (d, J=7.47 Hz, 1H) 8.38(dd, J=4.83, 1.76 Hz, 1H).

72F tert-Butyl (3-(isopropylsulfonyl)pyridin-2-yl)methylcarbamate

To a solution of 72E (560 mg, 1.98 mmol) and 1-tosyl-1H-imidazole (1.1g, 4.96 mmol) in MeOH (15 mL) at 0° C. was added 30% H₂O₂ (0.95 mL, 9.9mmol) and 1.0 N NaOH (4.36 mL, 4.36 mmol). After it was stirred at rtfor 2.0 h, MeOH was removed under reduced pressure. The crude wasextracted with EtOAc, washed with brine and dried over Na₂SO₄ andpurified by column chromatography to give 560 mg (90%) of 72F as aviscous oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.31 (d, J=7.03 Hz, 6H)1.40-1.46 (m, 9H) 4.80 (d, J=5.71 Hz, 2H) 5.85 (s, 1H) 7.41 (dd, J=7.91,4.83 Hz, 1H) 8.23 (dd, J=7.91, 1.76 Hz, 1H) 8.77 (dd, J=4.83, 1.76 Hz,1H).

72G (3-Iisopropylsulfonyl)pyridin-2-yl)methanamine HCl salt

To a solution of 72F (770 mg, 2.5 mmol) in EtOAc (5.0 mL) was added 4.0N HCl in dioxane (12.3 mL, 49 mmol). The mixture was stirred at rt for45 min. After removal of solvent, white solid product 72G was obtainedas HCl salt. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.30 (d, J=6.59 Hz, 6H)3.49 (t, J=6.59 Hz, 1H) 4.72 (s, 2H) 7.70 (dd, J=7.91, 4.83 Hz, 1H) 8.37(dd, J=7.91, 1.76 Hz, 1H) 8.92 (dd, J=4.83, 1.76 Hz, 1H); LC-MS 215(M+H).

72H

Example 72 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 72G. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.22(dd, J=7.03, 2.64 Hz, 6H) 1.28 (d, J=5.71 Hz, 6H) 1.37 (t, J=6.81 Hz,3H) 3.58-3.65 (m, 1H) 4.04 (q, J=7.03 Hz, 2H) 4.48-4.55 (m, 1H) 5.16 (s,1H) 6.74 (d, J=2.20 Hz, 1H) 6.85 (d, J=7.03 Hz, 1H) 6.95 (d, J=8.35 Hz,1H) 7.09 (dd, J=8.35, 2.20 Hz, 1H) 7.16 (d, J=2.20 Hz, 1H) 7.19 (dd,J=9.23, 2.20 Hz, 1H) 7.32 (d, J=7.03 Hz, 1H) 7.51 (dd, J=8.13, 4.61 Hz,1H) 8.07 (d, J=9.23 Hz, 1H) 8.22-8.25 (m, 1H) 8.70 (dd, J=4.83, 1.76 Hz,1H).

Example 73N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-phenyl)-acetamidetrifluoroacetic acid salt

73A2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluorophenyl)aceticacid

A mixture of 5-ethoxy-2-fluorophenylboronic acid (43 mg, 0.23 mmol),Intermediate 1 (72 mg, 0.2 mmol) and glyoxylic acid monohydrate (21 mg,0.23 mmol) in acetonitrile (0.7 mL) and DMF (0.07 mL) was heated at 85°C. for 30 min in a Microwave Reactor. The crude product was purified byflash column chromatography (CH₂Cl₂:MeOH=100:15) to give 28 mg (25%) of73A as a solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.14 (s, 18H) 1.19(t, J=6.81 Hz, 3H) 3.83 (q, J=7.03 Hz, 2H) 5.39 (s, 1H) 6.59 (d, J=2.20Hz, 1H) 6.70-6.77 (m, 1H) 6.89-7.00 (m, 2H) 7.16 (dd, J=9.23, 2.20 Hz,1H) 7.33 (d, J=5.71 Hz, 1H) 7.52 (d, J=9.23 Hz, 1H) 7.85 (s, 1H) 7.91(d, J=6.15 Hz, 1H); LC MS 556 (M+H).

73B

Example 73 was prepared according to the general coupling-deprotectionusing 73A and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.09(t, J=7.25 Hz, 3H) 1.23 (t, J=7.03 Hz, 3H) 2.05 (s, 3H) 3.13-3.22 (m,2H) 3.73-3.89 (m, 2H) 4.55-4.71 (m, 2H) 5.37 (s, 1H) 6.58 (d, J=2.20 Hz,1H) 6.71 (d, J=7.03 Hz, 1H) 6.77-6.85 (m, 2H) 6.95-7.05 (m, 1H) 7.09(dd, J=9.01, 2.42 Hz, 1H) 7.23 (d, J=7.03 Hz, 1H) 7.51-7.66 (m, 1H) 7.69(d, J=8.79 Hz, 2H) 7.99 (d, J=9.23 Hz, 1H) 8.56 (t, J=6.15 Hz, 1H); LCMS 594 (M+H).

Example 74N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-3-hydroxy-phenyl)-acetamidetrifluoroacetic acid salt

74A 5-Ethoxy-2-fluorophenol

To 4-ethoxy-1-fluorobenzene (1.0 g, 7.1 mmol) in THF (8.0 mL) was addedfreshly distilled N,N,N′,N″,N″-pentamethyldiethylenetriamine (0.8 mL)and 1.6 M n-butyllithium in hexane (5.13 ml, 8.2 mmol) at −78° C. Afterstirred at −60° C. for 1 h, trimethylborate (0.52 mL, 4.6 mmol) wasintroduced at −78° C. and the solution was warmed up to rt for 2 h. Thereaction was quenched by acetic acid (1.5 ml) at 0° C. After 15 min, 30%hydrogen peroxide (1.2 ml) was introduced and the mixture was stirredfrom 0° C. to rt overnight. The mixture was extracted by EtOAc (3×30mL). The combined organic layer was washed by brine, dried over MgSO₄,and concentrated. The crude product was purified by columnchromatography to give 1.0 g colorless oil of 74A. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.39 (t, J=6.81 Hz, 3 H) 3.96 (q, J=7.03 Hz, 2H) 5.30 (d,J=2.20 Hz, 1H) 6.28-6.43 (m, 1H) 6.55 (dd, J=7.47, 3.08 Hz, 1H)6.90-7.01 (m, 1H).

74B tert-Butyl(5-ethoxy-2-fluorophenoxy)dimethylsilane

To 74A (1.0 g, 6.4 mmol) in DMF (20 mL) was added imidazole (0.6 g, 8.8mmol) and t-butyl chlorodimethylsilane (2.0 g, 12.8 mmol) and themixture was stirred at rt overnight. The reaction was diluted by EtOAc(100 mL) and washed by water (100 mL) and brine (50 mL). The organiclayer was dried over MgSO₄ and concentrated. The crude product waspurified by column chromatography to give 1.15 g of 74B (67% yield). ¹HNMR (400 MHz, CDCl₃) δ ppm 0.19 (s, 6H) 1.00 (s, 9H) 1.39 (t, J=6.81 Hz,3H) 3.95 (q, J=7.03 Hz, 2H) 6.37-6.44 (m, 1H) 6.46 (dd, J=7.03, 3.08 Hz,1H) 6.78-7.06 (m, 1H).

74C 3-(tert-Butyldimethylsilyloxy)-5-ethoxy-2-fluorophenylboronic acid

To 74B (110 mg, 0.4 mmol) in THF (1.5 mL) was added freshly distilledN,N,N′,N″,N″-pentamethyldiethylenetriamine (0.2 mL) and 1.6 Mn-butyllithium in hexane (0.5 mL, 0.8 mmol) at −78° C. After stirred at−35° C. for 1.5 h, trimethylborate (0.23 mL, 2.0 mmol) was introduced at−78° C., the solution was warmed up to rt overnight. The reaction wasquenched by 1.0 N HCl (1.5 mL). After 30 min, the mixture was extractedby EtOAc (3×15 mL). The combined organic layer was washed by brine,dried over MgSO₄, and concentrated. The crude product was purified bycolumn chromatography to give 90 mg white solid of 74C (72% yield). ¹HNMR (400 MHz, Methanol-d₄) δ ppm 0.19 (s, 6H) 1.00 (s, 9H) 1.39 (t,J=7.03 Hz, 3H) 4.00 (q, J=7.03 Hz, 2H) 5.17 (d, J=6.59 Hz, 2H) 6.59 (dd,J=7.47, 3.08 Hz, 1H) 6.86 (t, J=3.52 Hz, 1H).

74D2-(1-(tert-Butoxycarbonyl)isoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-3-hydroxyphenyl)aceticacid

A mixture 74C, Intermediate 1 (72 mg, 0.2 mmol) and glyoxylic acidmonohydrate (21 mg, 0.23 mmol) in acetonitrile (0.7 mL) and DMF (0.07mL) was heated at 85° C. for 30 min in a Microwave Reactor. The crudeproduct was purified by flash column chromatography (CH₂Cl₂:MeOH=100:15)to give 28 mg (25%) of 74D as a solid. ¹H NMR (400 MHz, Methanol-d₄) δppm 0.92 (s, 9H) 1.22 (t, J=7.03 Hz, 3H) 3.82 (q, J=7.03 Hz, 2H) 5.45(s, 1H) 6.36 (dd, J=6.59, 3.08 Hz, 1H) 6.48-6.53 (m, 1H) 6.60 (d, J=2.20Hz, 1H) 6.74 (d, J=7.03 Hz, 1H) 7.11 (d, J=2.64 Hz, 1H) 7.22 (d, J=7.03Hz, 1H) 7.99 (d, J=9.23 Hz, 1H).

74E

Example 74 was prepared according to the general coupling-deprotectionusing 74D and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.21 (t, J=7.03 Hz, 3H) 2.00 (s, 3H)3.67-3.88 (m, 2H) 4.30 (d, J=5.27 Hz, 2H) 5.34 (s, 1H) 6.30-6.42 (m, 2H)6.62 (d, J=2.20 Hz, 1H) 6.74 (d, J=7.03 Hz, 1H) 6.87 (d, J=7.47 Hz, 1H)7.05-7.31 (m, 4H) 7.38 (s, 1H) 8.00 (d, J=9.23 Hz, 1H) 8.72 (t, J=6.15Hz, 1H); LC MS 518 (M+H).

Example 75N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-phenyl)-acetamidetrifluoroacetic acid salt

Example 75 was prepared according to the general coupling-deprotectionusing 73A and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.23 (t, J=6.81 Hz, 3H) 1.99 (s, 3H)3.74-3.92 (m, 2H) 4.30 (dd, J=5.71, 2.64 Hz, 2H) 5.36 (s, 1H) 6.62 (d,J=2.20 Hz, 1H) 6.73 (d, J=7.03 Hz, 1H) 6.77-6.93 (m, 3H) 7.00 (t, J=9.23Hz, 1H) 7.04-7.14 (m, 2H) 7.21-7.32 (m, 2H) 7.38 (s, 1H) 8.00 (d, J=9.23Hz, 1H) 8.77 (t, J=5.93 Hz, 1H); LC MS 502 (M+H).

Example 762-(1-Amino-isoquinolin-6-ylamino)-N-(2-cyclopropanesulfonyl-benzyl)-2-(5-ethoxy-2-fluoro-phenyl)-acetamidetrifluoroacetic acid salt

Example 76 was prepared according to the general coupling-deprotectionusing 73A and Intermediate 7. ¹H NMR (400 MHz, Methanol-d₄) δ ppm0.90-0.98 (m, 2H) 1.01-1.15 (m, 2H) 1.24 (t, J=7.03 Hz, 3H) 2.75-2.84(m, 1H) 3.76-3.91 (m, 2H) 4.68-4.88 (m, 2H) 6.62 (d, J=2.20 Hz, 1H) 6.74(d, J=7.03 Hz, 1H) 6.78-6.89 (m, 2H) 7.01 (t, J=9.23 Hz, 1H) 7.10 (dd,J=9.23, 2.64 Hz, 1H) 7.25 (d, J=7.03 Hz, 1H) 7.34-7.49 (m, 3H) 7.71-7.77(m, 1H) 8.00 (d, J=9.23 Hz, 2H) 8.60 (t, J=6.15 Hz, 1H); LC MS 549(M+H).

Example 77N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2-chloro-5-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

77A2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(2-chloro-5-methoxyphenyl)aceticacid

A mixture of 2-chloro-5-methoxyhenylboronic acid (43 mg, 0.23 mmol),Intermediate 1 (72 mg, 0.2 mmol) and glyoxylic acid monohydrate (21 mg,0.23 mmol) in acetonitrile (0.7 mL) and DMF (0.07 mL) was heated at 85°C. for 30 min in a Microwave Reactor. The crude product was purified byflash column chromatography (CH₂Cl₂:MeOH=100:15) to give 28 mg (25%) of77A as a solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.16 (s, 18H) 3.24(s, 3H) 5.55 (s, 1H) 6.57 (d, J=2.20 Hz, 1H) 6.75-6.84 (m, 2H) 7.00 (d,J=3.08 Hz, 1H) 7.10-7.20 (m, 1H) 7.27 (d, J=9.23 Hz, 1H) 7.32 (d, J=5.27Hz, 1H) 7.54 (d, J=9.23 Hz, 1H) 7.93 (d, J=6.15 Hz, 1H); LC MS 558(M+H).

77B

Example 77 was prepared according to the general coupling-deprotectionusing 77A and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 2.00 (s, 3H) 3.61 (s, 3H) 4.33 (d,J=5.71 Hz, 2H) 5.47 (s, 1H) 6.60 (d, J=2.20 Hz, 1H) 6.74 (d, J=7.03 Hz,1H) 6.84 (dd, J=8.79, 3.08 Hz, 1H) 6.89 (d, J=7.47 Hz, 1H) 6.94 (d,J=2.64 Hz, 1H) 7.06-7.14 (m, 2H) 7.22-7.31 (m, 3H) 7.42 (s, 1H) 8.00 (d,J=9.23 Hz, 1H) 8.76 (t, J=5.93 Hz, 1H); LC MS 504 (M+H).

Example 78N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2-chloro-5-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 78 was prepared according to the general coupling-deprotectionusing 77A and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.09(t, J=7.47 Hz, 3H) 2.05 (s, 3H) 3.14-3.21 (m, 2H) 3.59 (s, 3H) 4.63 (t,J=5.05 Hz, 2H) 5.47 (s, 1H) 6.56 (d, J=2.20 Hz, 1H) 6.70 (d, J=7.03 Hz,1H) 6.80-6.86 (m, 2H) 7.07 (dd, J=9.23, 2.20 Hz, 1H) 7.22 (d, J=7.03 Hz,1H) 7.28 (d, J=8.35 Hz, 1H) 7.54 (dd, J=8.35, 2.20 Hz, 1H) 7.69 (d,J=8.79 Hz, 1H) 7.76 (d, J=2.20 Hz, 1H) 7.99 (d, J=9.23 Hz, 1H) 8.52 (t,J=5.93 Hz, 1H); LC MS 596 (M+H).

Example 79N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(4-chloro-3-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

79A 4-Chloro-3-methoxyphenylboronic acid

To 4-bromo-1-chloro-2-methoxybenzene (2.2 g, 9.9 mmol) in toluene/THF(16/6 mL) at −78° C. was added n-butyl lithium (8.7 mL, 1.6 M in hexane,14 mmol) dropwise. The reaction was stirred at −78° C. for 30 min., thentrimethylborate (2.2 mL, 19.8 mmol) was added. The reaction was allowedto warm to rt and stirred overnight and then quenched with 1 M HCl (15mL). The organic layer was separated and dried over sodium sulfate. Thesolvent was removed and the crude product was purified by flash columnchromatography to give 79A (1.2 g, 65% yield) as a white solid. ¹H NMR(400 MHz, Methanol-d₄) δ ppm 3.87 (m, 3H) 7.11 (d, J=7.83 Hz, 1H) 7.20(s, 1H) 7.29 (d, J=7.83 Hz, 1H).

79B2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-chloro-3-methoxyphenyl)aceticacid

A mixture of 79A (43 mg, 0.23 mmol), Intermediate 1 (72 mg, 0.2 mmol)and glyoxylic acid monohydrate (21 mg, 0.23 mmol) in acetonitrile (0.7mL) and DMF (0.07 mL) was heated at 85° C. for 30 min in a MicrowaveReactor. The crude product was purified by flash column chromatography(CH₂Cl₂:MeOH=100:15) to give 56 mg (50%) of 79B as a solid. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.18 (s, 18H) 3.78 (s, 3H) 6.56 (d, J=2.20 Hz,1H) 7.05 (d, J=8.35 Hz, 1H) 7.17 (dd, J=8.79, 2.20 Hz, 1H) 7.20-7.25 (m,3H) 7.32 (d, J=5.71 Hz, 1H) 7.53 (d, J=9.23 Hz, 1H) 7.92 (d, J=5.71 Hz,1H); LC MS 558 (M+H).

79C

Example 79 was prepared according to the general coupling-deprotectionusing 79B and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.99 (s, 3H) 3.73 (s, 3H) 4.28 (d,J=5.27 Hz, 2H) 5.04 (s, 1H) 6.56 (d, J=2.20 Hz, 1H) 6.70 (d, J=7.03 Hz,1H) 6.81 (d, J=7.03 Hz, 1H) 7.00 (dd, J=8.13, 1.98 Hz, 1H) 7.05-7.12 (m,3H) 7.20-7.30 (m, 3H) 7.34 (s, 1H) 7.99 (d, J=9.23 Hz, 1H) 8.78 (t,J=5.71 Hz, 1H); LC MS 504 (M+H).

Example 802-(1-Amino-isoquinolin-6-ylamino)-2-(4-chloro-3-methoxy-phenyl)-N-(2-cyclopropanesulfonyl-benzyl)-acetamidetrifluoroacetic acid salt

Example 80 was prepared according to the general coupling-deprotectionusing 79B and Intermediate 7. ¹H NMR (400 MHz, Methanol-d₄) δ ppm0.86-0.97 (m, 2H) 1.00-1.18 (m, 2H) 2.64-2.81 (m, 1H) 3.75 (s, 3H)4.64-4.89 (m, 2H) 5.11 (s, 1H) 6.57 (d, J=2.64 Hz, 1H) 6.72 (d, J=7.03Hz, 1H) 7.00 (dd, J=8.13, 1.98 Hz, 1H) 7.06-7.14 (m, 2H) 7.20-7.31 (m,3H) 7.31-7.44 (m, 2H) 7.73 (d, J=9.23 Hz, 1H) 7.99 (d, J=9.23 Hz, 1H)8.58 (t, J=6.15 Hz, 1H); LC MS 551 (M+H).

Example 81N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(4-chloro-3-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 81 was prepared according to the general coupling-deprotectionusing 79B and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.07(t, J=7.25 Hz, 3H) 2.03 (s, 3H) 3.11-3.32 (m, 2H) 3.73 (s, 3H) 4.47-4.70(m, 2H) 5.08 (s, 1H) 6.52 (d, J=2.64 Hz, 1H) 6.68 (d, J=7.03 Hz, 1H)6.98 (dd, J=8.13, 1.98 Hz, 1H) 7.04-7.12 (m, 2H) 7.21 (d, J=7.03 Hz, 1H)7.26 (d, J=8.35 Hz, 1H) 7.47 (dd, J=8.79, 2.20 Hz, 1H) 7.62-7.72 (m, 2H)7.97 (d, J=9.23 Hz, 1H) 8.58 (t, J=6.15 Hz, 1H); LC MS 596 (M+H).

Example 82N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2-fluoro-5-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

82A2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-fluorophenyl)aceticacid

A mixture of 2-fluoro-5-methoxyphenylboronic acid (38 mg, 0.23 mmol),Intermediate 1 (72 mg, 0.2 mmol) and glyoxylic acid monohydrate (21 mg,0.23 mmol) in acetonitrile (0.7 mL) and DMF (0.07 mL) was heated at 85°C. for 30 min in a Microwave Reactor. The crude product was purified byflash column chromatography (CH₂Cl₂:MeOH=100:15) to give 27 mg (25%) of82A as a solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.17 (s, 18H) 3.63(s, 3H) 5.43 (s, 1H) 6.62 (d, J=2.20 Hz, 1H) 6.74-6.91 (m, 2H) 6.93-7.04(m, 2H) 7.18 (dd, J=9.23, 2.20 Hz, 1H) 7.36 (d, J=5.71 Hz, 1H) 7.54 (d,J=9.23 Hz, 1H) 7.94 (d, J=5.71 Hz, 1H); LC MS 542 (M+H).

82B

Example 82 was prepared according to the general coupling-deprotectionusing 82A and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.98 (s, 3H) 3.61 (s, 3H) 4.29 (d,J=5.71 Hz, 2H) 5.36 (s, 1H) 6.61 (d, J=2.20 Hz, 1H) 6.72 (d, J=7.47 Hz,1H) 6.78-6.88 (m, 2H) 6.92 (dd, J=5.71, 3.08 Hz, 1H) 7.00 (t, J=9.23 Hz,1H) 7.04-7.12 (m, 2H) 7.19-7.29 (m, 2H) 7.37 (s, 1H) 7.99 (d, J=9.23 Hz,1H) 8.78 (t, J=5.93 Hz, 1H); LC MS 488 (M+H).

Example 832-(1-Amino-isoquinolin-6-ylamino)-N-(2-cyclopropanesulfonyl-benzyl)-2-(2-fluoro-5-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 83 was prepared according to the general coupling-deprotectionusing 82A and Intermediate 7. ¹H NMR (400 MHz, Methanol-d₄) δ ppm0.88-0.97 (m, 2H) 0.99-1.15 (m, 2H) 2.64-2.95 (m, 1H) 3.62 (s, 3H)4.66-4.91 (m, 2H) 5.39 (s, 1H) 6.61 (d, J=2.20 Hz, 1H) 6.73 (d, J=7.03Hz, 1H) 6.80-6.86 (m, 1H) 6.89 (dd, J=5.71, 3.08 Hz, 1H) 7.02 (t, J=9.23Hz, 1H) 7.09 (dd, J=9.01, 2.42 Hz, 1H) 7.24 (d, J=7.03 Hz, 1H) 7.33-7.40(m, 2H) 7.44 (t, J=6.81 Hz, 1H) 7.70-7.75 (m, 1H) 8.00 (d, J=9.23 Hz,1H) 8.60 (t, J=5.93 Hz, 1H); LC MS 535 (M+H).

Example 84N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2-fluoro-5-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 84 was prepared according to the general coupling-deprotectionusing 82A and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.08(t, J=7.47 Hz, 3H) 2.03 (s, 3H) 3.11-3.21 (m, 2H) 3.60 (s, 3H) 4.51-4.71(m, 2H) 5.37 (s, 1H) 6.56 (d, J=2.20 Hz, 1H) 6.69 (d, J=7.03 Hz, 1H)6.77-6.86 (m, 2H) 7.00 (t, J=9.01 Hz, 1H) 7.08 (dd, J=9.23, 2.20 Hz, 1H)7.21 (d, J=7.03 Hz, 1H) 7.53 (dd, J=8.79, 2.20 Hz, 1H) 7.65-7.71 (m, 2H)7.98 (d, J=9.23 Hz, 1H) 8.57 (t, J=5.93 Hz, 1H); LC MS 580 (M+H).

Example 85N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2-fluoro-5-propoxy-phenyl)-acetamidetrifluoroacetic acid salt

85A2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(2-fluoro-5-propoxyphenyl)aceticacid

A mixture of 2-fluoro-5-propoxyphenylboronic acid (45 mg, 0.23 mmol),Intermediate 1 (72 mg, 0.2 mmol) and glyoxylic acid monohydrate (21 mg,0.23 mmol) in acetonitrile (0.7 mL) and DMF (0.07 mL) was heated at 85°C. for 30 min in a Microwave Reactor. The crude product was purified byflash column chromatography (CH₂Cl₂:MeOH=100:15) to give 29 mg (25%) of85A as a solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 0.87 (t, J=7.25 Hz,3H) 1.17 (s, 18H) 1.61 (q, J=6.59 Hz, 2H) 3.74 (t, J=6.37 Hz, 2H) 5.25(s, 1H) 6.58 (d, J=1.76 Hz, 1H) 6.66-6.77 (m, 1H) 6.90-7.01 (m, 2H) 7.14(dd, J=9.01, 1.98 Hz, 1H) 7.31 (d, J=6.15 Hz, 1H) 7.52 (d, J=9.23 Hz,1H) 7.92 (d, J=5.71 Hz, 1H); LC MS 570 (M+H).

85B

Example 85 was prepared according to the general coupling-deprotectionusing 85A and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 0.89 (t, J=7.47 Hz, 3H) 1.55-1.71 (m,2H) 1.98 (s, 3H) 3.66-3.77 (m, 2H) 4.25-4.35 (m, 2H) 5.35 (s, 1H) 6.61(d, J=2.20 Hz, 1H) 6.71 (d, J=7.03 Hz, 1H) 6.77-6.83 (m, 1H) 6.85 (d,J=7.91 Hz, 1H) 6.89 (dd, J=5.71, 3.08 Hz, 1H) 6.99 (t, J=9.23 Hz, 1H)7.03-7.12 (m, 2H) 7.19-7.29 (m, 2H) 7.37 (s, 1H) 7.99 (d, J=9.23 Hz, 1H)8.78 (t, J=5.93 Hz, 1H); LC MS 516 (M+H).

Example 86N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2-fluoro-5-propoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 86 was prepared according to the general coupling-deprotectionusing 85A and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm0.83-0.95 (m, 3H) 0.98-1.13 (m, 3H) 1.55-1.70 (m, 2H) 2.03 (s, 3H)3.10-3.10 (m, 2H) 3.60-3.79 (m, 2H) 4.52-4.71 (m, 2H) 5.36 (s, 1H) 6.57(d, J=2.20 Hz, 1H) 6.69 (d, J=7.47 Hz, 1H) 6.76-6.84 (m, 2H) 6.94-7.03(m, 1H) 7.07 (dd, J=9.23, 2.20 Hz, 1H) 7.21 (d, J=7.47 Hz, 1H) 7.53-7.59(m, 1H) 7.68 (d, J=8.79 Hz, 2H) 7.94-8.01 (m, 1H) 8.56 (t, J=5.93 Hz,1H); LC MS 608 (M+H).

Example 87N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2-fluoro-5-methyl-phenyl)-acetamidetrifluoroacetic acid salt

87A2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(2-fluoro-5-methylphenyl)aceticacid

A mixture of 2-fluoro-5-methylphenylboronic acid (34 mg, 0.23 mmol),Intermediate 1 (72 mg, 0.2 mmol) and glyoxylic acid monohydrate (21 mg,0.23 mmol) in acetonitrile (0.7 mL) and DMF (0.07 mL) was heated at 85°C. for 30 min. in a Microwave Reactor. The crude product was purified byflash column chromatography (CH₂Cl₂:MeOH=100:15) to give 52 mg (50%) of87A as a solid. ¹ H NMR (400 MHz, Methanol-d₄) δ ppm 1.18 (s, 18H) 2.19(s, 3H) 5.44 (s, 1H) 6.62 (d, J=2.20 Hz, 1H) 6.93-7.00 (m, 1H) 7.03-7.09(m, 1H) 7.19 (dd, J=9.23, 2.20 Hz, 1-H) 7.22-7.27 (m, 1H) 7.37 (d,J=5.71 Hz, 1H) 7.55 (d, J=9.23 Hz, 1H) 7.95 (d, J=5.71 Hz, 1H); LC MS526 (M+H).

87B

Example 87 was prepared according to the general coupling-deprotectionusing 87A and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.98 (s, 3H) 2.18 (s, 3H) 4.29 (d,J=6.15 Hz, 2H) 5.35 (s, 1H) 6.60 (d, J=2.20 Hz, 1H) 6.72 (d, J=7.03 Hz,1H) 6.84 (d, J=7.47 Hz, 1H) 6.92-7.01 (m, 1H) 7.04-7.12 (m, 3H)7.16-7.28 (m, 3H) 7.38 (s, 1H) 7.98 (d, J=9.23 Hz, 1H) 8.76 (t, J=5.93Hz, 1H); LC MS 472 (M+H).

Example 88N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(2-fluoro-5-methyl-phenyl)-acetamidetrifluoroacetic acid salt

Example 88 was prepared according to the general coupling-deprotectionusing 87A and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.08(t, J=7.47 Hz, 3H) 2.04 (s, 3H) 2.17 (s, 3H) 3.14 (s, 2H) 4.61 (t,J=5.27 Hz, 2H) 5.35 (s, 1H) 6.55 (d, J=2.20 Hz, 1H) 6.68 (d, J=7.03 Hz,1H) 6.89-7.01 (m, 1H) 7.05-7.16 (m, 3H) 7.21 (d, J=7.03 Hz, 1H) 7.53(dd, J=8.57, 1.98 Hz, 1H) 7.67 (d, J=8.79 Hz, 1H) 7.73 (d, J=1.76 Hz,1H) 7.97 (d, J=9.23 Hz, 1H) 8.56 (t, J=5.93 Hz, 1H); LC MS 564 (M+H).

Example 89N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(5-ethyl-2-fluoro-phenyl)-acetamidetrifluoroacetic acid salt

89A 1-(3-Bromo-4-fluorophenyl)ethanol

To a solution of 3-bromo-4-fluoroacetophenone (10 g, 46 mmol) in THF(100 mL) and methanol (1.0 mL) was added sodium borohydride (2.1 g, 55.5mmol). The mixture was heated up to 70° C. for 1 h, then cooled down tort. The reaction was quenched by 100 ml of 1N HCl solution and extractedby EtOAc (3×100 mL). The combined organic layer was washed by brine,dried over MgSO₄, and concentrated. The crude product was purified bycolumn chromatography to give 9.8 g of 89A (97% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.48 (d, J=6.15 Hz, 3H) 7.24-7.33 (m, 1H) 7.59 (dd, J=6.59,2.20 Hz, 1H).

89B 2-Bromo-4-ethyl-1-fluorobenzene

To 89A (9.8 g, 45 mmol) in trifluoroacetic acid (20 mL) was addedtriethylsilane (14.3 mL, 90 mmol). After stirring at 50° C. for 6 h, thereaction was quenched by 100 mL of saturated NaHCO₃ solution andextracted by diethyl ether (3×). The combined organic layer was washedby brine, dried by MgSO₄, and concentrated. The crude residual wasdistilled at 200° C. to give 89B (85% purity). ¹H NMR (400 MHz, CDCl₃) δppm 1.22 (t, J=7.69 Hz, 3H) 2.60 (q, J=7.47 Hz, 2H) 7.02 (t, J=8.57 Hz,1H) 7.06-7.12 (m, 1H) 7.37 (dd, J=6.59, 2.20 Hz, 1H).

89C 5-Ethyl-2-fluorophenylboronic acid

To 89B (550 mg, 2.3 mmol) in THF (10 mL) was added 1.6 M n-butyllithiumin hexane (2.2 ml, 3.5 mmol) at −78° C. After stirred for 1 h,trimethylborate (0.52 mL, 4.6 mmol) was introduced at −78° C. Thereaction mixture was warmed up to room temperature overnight. It wasthen quenched by 1.0 N HCl (10 mL) and extracted by EtOAc (3×30 mL). Thecombined organic layer was washed by brine, dried over MgSO₄, andconcentrated. The crude product was purified by column chromatography togive 255 mg white solid of 89C. ¹H NMR (400 MHz, Methanol-d₄) δ ppm1.15-1.27 (m, 3H) 2.61 (q, J=7.76 Hz, 2H) 6.94 (t, J=8.57 Hz, 1H)7.17-7.27 (m, 2H).

89D2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(5-ethyl-2-fluoro-phenyl)aceticacid

A mixture of 89C (36 mg, 0.23 mmol), Intermediate 1 (72 mg, 0.2 mmol)and glyoxylic acid monohydrate (21 mg, 0.23 mmol) in acetonitrile (0.7mL) and DMF (0.07 mL) was heated at 85° C. for 30 min in a MicrowaveReactor. The crude product was purified by flash column chromatography(CH₂Cl₂:MeOH=100:15) to give 54 mg (51% yield) of 89D as a solid. ¹H NMR(400 MHz, Methanol-d₄) δ ppm 1.05 (t, J=7.47 Hz, 3H) 1.16 (s, 18H) 2.48(q, J=7.62 Hz, 2H) 5.44 (s, 1H) 6.61 (d, J=2.20 Hz, 1H) 6.93-7.00 (m,1H) 7.03-7.10 (m, 1H) 7.18 (dd, J=9.23, 2.20 Hz, 1H) 7.25 (dd, J=7.03,2.20 Hz, 1H) 7.35 (d, J=5.71 Hz, 1H) 7.54 (d, J=9.23 Hz, 1H) 7.93 (d,J=6.15 Hz, 1H) LC MS 540 (M+H).

89E

Example 89 was prepared according to the general coupling-deprotectionusing 89D and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.07 (t, J=7.69 Hz, 3H) 1.94-2.06 (m,3H) 2.49 (q, J=7.76 Hz, 2H) 4.30 (d, J=6.15 Hz, 2H) 5.36 (s, 1H) 6.62(d, J=2.20 Hz, 1H) 6.73 (d, J=7.03 Hz, 1H) 6.85 (d, J=7.47 Hz, 1H)6.95-7.02 (m, 1H) 7.04-7.16 (m, 3H) 7.19-7.30 (m, 3H) 7.40 (s, 1H) 7.99(d, J=9.23 Hz, 1H) 8.78 (t, J=5.93 Hz, 1H); LC MS 486 (M+H).

Example 90N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(5-ethyl-2-fluoro-phenyl)-acetamidetrifluoroacetic acid salt

Example 90 was prepared according to the general coupling-deprotectionusing 89D and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm1.01-1.10 (m, 6H) 2.04 (s, 3H) 2.46 (q, J=7.47 Hz, 2H) 3.11-3.21 (m, 2H)4.61 (d, J=6.15 Hz, 2H) 5.35 (s, 1H) 6.56 (d, J=2.20 Hz, 1H) 6.69 (d,J=7.03 Hz, 1H) 6.98 (t, J=9.67 Hz, 1H) 7.04-7.15 (m, 3H) 7.22 (d, J=7.03Hz, 1H) 7.55 (dd, J=8.79, 2.20 Hz, 1H) 7.67 (d, J=8.35 Hz, 1H) 7.73 (d,J=2.20 Hz, 1H) 7.98 (d, J=8.79 Hz, 1H) 8.56 (t, J=6.15 Hz, 1H); LC MS578 (M+H).

Example 91N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(4-chloro-3-ethyl-phenyl)-acetamidetrifluoroacetic acid salt

91A2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethyl-phenyl)aceticacid

A mixture of 4-chloro-3-ethylphenylboronic acid (38 mg, 0.23 mmol),Intermediate 1 (72 mg, 0.2 mmol) and glyoxylic acid monohydrate (21 mg,0.23 mmol) in acetonitrile (0.7 mL) and DMF (0.07 mL) was heated at 85°C. for 30 min in a Microwave Reactor. The crude product was purified byflash column chromatography (CH₂Cl₂:MeOH=100:15) to give 54 mg (50%) of91A as a solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.07 (t, J=7.69 Hz,3H) 1.16 (s, 18H) 2.63 (q, J=7.47 Hz, 2H) 5.11 (s, 1H) 6.56 (d, J=2.20Hz, 1H) 7.18 (dd, J=9.23, 2.20 Hz, 1H) 7.21-7.24 (m, 1H) 7.26-7.33 (m,2H) 7.40 (d, J=2.20 Hz, 1H) 7.53 (d, J=9.23 Hz, 1H) 7.91 (d, J=5.71 Hz,1H); LC MS 556 (M+H).

91B

Example 91 was prepared according to the general coupling-deprotectionusing 91A and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.09 (t, J=7.69 Hz, 3H) 1.99 (s, 3H)2.62-2.73 (m, 2H) 4.27 (d, J=5.71 Hz, 2H) 5.03 (s, 1H) 6.54 (d, J=2.20Hz, 1H) 6.68 (d, J=7.03 Hz, 1H) 6.79 (d, J=7.47 Hz, 1H) 7.02-7.12 (m,2H) 7.19-7.30 (m, 4H) 7.35 (d, J=3.08 Hz, 2H) 7.98 (d, J=9.23 Hz, 1H)8.79 (t, J=5.71 Hz, 1H); LC MS 502 (M+H).

Example 92N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(4-chloro-3-ethyl-phenyl)-acetamidetrifluoroacetic acid salt

Example 92 was prepared according to the general coupling-deprotectionusing 91A and Intermediate 9. ¹H NMR (400 MHz, Methanol-d₄) δ ppm1.02-1.14 (m, 6H) 2.03 (s, 3H) 2.63 (q, J=7.47 Hz, 2H) 3.11-3.21 (m, 2H)4.46-4.69 (m, 2H) 5.06 (s, 1H) 6.50 (d, J=2.20 Hz, 1H) 6.66 (d, J=7.03Hz, 1H) 7.07 (dd, J=9.23, 2.20 Hz, 1H) 7.17-7.33 (m, 4H) 7.49 (dd,J=8.79, 2.20 Hz, 1H) 7.62-7.72 (m, 2H) 7.96 (d, J=9.23 Hz, 1H) 8.58 (t,J=5.93 Hz, 1H); LC MS 594 (M+H).

Example 932-(1-Amino-isoquinolin-6-ylamino)-N-(2-cyclobutanesulfonyl-benzyl)-2-(3-ethoxy-4-fluoro-phenyl)-N-methyl-acetamidetrifluoroacetic acid salt

Example 93 was prepared according to the general coupling-deprotectionusing 64D and Intermediate 12. ¹H NMR (400 MHz, Methanol-d₄) δ ppm amixture of two rotomers: 1.30 (m, 3H) 1.90-2.41 (m, 6H) 2.96 and 3.11(s, 3H) 3.90-4.10 (m, 3H) 4.76 (m, 1H), 5.04-5.19 (m, 2H) 5.53 and 5.72(s, 1H) 6.60-7.41 (m, 11H) 7.83-8.00 (m, 2H); LC MS 577 (M+H).

Example 942-(1-Amino-isoquinolin-6-ylamino)-N-(2-cyclobutanesulfonyl-benzyl)-2-(5-ethoxy-2-fluoro-phenyl)-N-methyl-acetamidetrifluoroacetic acid salt

Example 94 was prepared according to the general coupling-deprotectionusing 73A and Intermediate 12. ¹H NMR (400 MHz, Methanol-d₄) δ ppm amixture of two rotomers: 1.25 (m, 3H) 1.90-2.42 (m, 6H) 2.93 and 3.05(s, 3H) 3.83-4.11 (m, 3H) 4.49-5.12 (m, 2H) 5.82-5.95 (s, 1H) 6.62-7.43(m, 10H) 7.79-7.86 (m, 1H) 7.94-8.01 (m, 1H) LC MS 577)M+H).

Example 952-(1-Amino-isoquinolin-6-ylamino)-2-(4-chloro-3-ethoxy-phenyl)-N-(2-cyclobutanesulfonyl-benzyl)-N-methyl-acetamidetrifluoroacetic acid salt

Example 95 was prepared according to the general coupling-deprotectionusing Intermediate 15 and Intermediate 12. ¹H NMR (400 MHz, Methanol-d₄)δ ppm a mixture of two rotomers: 1.32 (m, 3H) 1.90-2.42 (m, 6H) 2.97 and3.12 (s, 3H) 4.02 (m, 2H) 5.05-5.18 (s, 1H) 5.55 and 5.74 (s, 1H)6.61-7.37 (m, 10H) 7.83-8.00 (m, 2H); LC MS 593 (M+H).

Example 962-(1-Amino-isoquinolin-6-ylamino)-N-(3-difluoromethyl-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

96A 3-(Difluoromethyl)benzonitrile

To a solution of 3-nitrobenzaldehyde (262 mg, 2.0 mmol) indichloromethane (10 mL) was added (diethylamino)sulfur trifluoride(DAST, 0.31 mL, 2.4 mmol) at rt. After stirring for two hrs, thereaction was quenched by 10 mL of saturated NaHCO₃ solution, andextracted by dichloromethane (2×10 mL), the combined organic layer waswashed by brine, dried by MgSO₄, and concentrated. The crude product waspurified by column chromatography to give 200 mg (65% yield) colorlessliquid of 96A. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.68 (t, J=56.03 Hz, 1H)7.61 (t, J=7.69 Hz, 1H) 7.73-7.85 (m, 3H).

96B (3-(Difluoromethyl)phenyl)methanamine

To a solution of 96A (200 mg, 1.3 mmol) in methanol (5 mL) was added 10%Pd/C (50 mg) and 4.0 N HCl in dioxane (0.4 mL, 1.6 mmol). The mixturewas stirred under hydrogen balloon at room temperature for 2 h andfiltrated. The filtration was concentrated to a white solid of 96B asHCl salt (250 mg, 100% yield). ¹H NMR (400 MHz, Methanol-d₄) δ ppm 4.08(s, 2H) 6.71 (t, J=56.03 Hz, 1H) 7.45-7.53 (m, 3H) 7.57 (s, 1H).

96C

Example 96 was prepared according to the general coupling-deprotectionusing 96B and Intermediate 2. ¹H NMR (400 MHz, Methanol-d₄) 8 ppm 1.30(d, J=6.15 Hz, 6H) 1.36 (t, J=7.03 Hz, 3H) 3.96-4.03 (m, J=7.03, 7.03,6.81, 1.98 Hz, 2H) 4.36-4.41 (m, 1H) 4.49-4.56 (m, 2H) 5.07 (s, 1H) 6.66(d, J=2.20 Hz, 1H) 6.80 (d, J=7.03 Hz, 1H) 6.95-6.98 (m, 1H) 7.05-7.11(m, 2H) 7.19 (dd, J=9.23, 2.64 Hz, 1H) 7.26-7.38 (m, 6H) 8.08 (d, J=9.23Hz, 1H) 8.90 (t, J=6.15 Hz, 1H); LC MS 535 (M+H).

Example 972-(1-Amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-N-(3-methyl-benzyl)-acetamidetrifluoroacetic acid salt

Example 97 was prepared according to the general coupling-deprotectionusing Intermediate 4 and commercial m-tolylmethanamine. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 2.06 (s, 3H) 3.69 (s, 3H) 3.74 (s, 3H) 4.18-4.24 (m,1H) 4.30-4.36 (m, 1H) 4.99 (s, 1H) 6.58 (d, J=1.76 Hz, 1H) 6.71 (d,J=7.47 Hz, 1H) 6.75 (s, 1H) 6.83-6.91 (m, 3H) 6.98-7.04 (m, 3H) 7.11(dd, J=9.23, 1.76 Hz, 1H) 7.24 (d, J=7.03 Hz, 1H) 7.99 (d, J=9.23 Hz,1H) 8.70 (t, J=5.93 Hz, 1H); LC MS457(M+H).

Example 98(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-phenyl)-acetylamino]-3-(2-isopropylsulfanyl-5-methoxycarbonylamino-phenyl)-propionicacid methyl ester trifluoroacetic acid salt

98A(S,E)-N-(2-(Isopropylthio)-5-nitrobenzylidene)-4-methylbenzenesulfinamide

To 2-(isopropylthio)-5-nitrobenzaldehyde (234 mg, 1.0 mmol) and(S)-(+)-p-toluenesulfinamide (161 mg, 1.0 mmol) in CH₂Cl₂ (10 mL) wasadded Ti(OEt)₄ (25% tech, 0.54 mL). The mixture was heated at 75° C. for3.0 h. TLC indicated a clean reaction. Solvent was removed and theresidue was redissolved in EtOAc, under stirring sat. Na₂SO₄ solutionwas added and the slurry was stirred at rt for 30 min before it wasfiltered through a pad of Celite®. The filtrate was extracted withEtOAc, washed with brine and dried over Na₂SO₄. After evaporation ofsolvent, 98A (320 mg, 88% yield) was obtained as a solid used for nextstep without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.34(d, J=6.59 Hz, 6H) 2.34 (s, 3H) 3.51-3.61 (m, 1H) 7.27 (d, J=7.91 Hz,2H) 7.45 (d, J=8.79 Hz, 1H) 7.59 (d, J=8.35 Hz, 2H) 8.14 (dd, J=8.79,2.64 Hz, 1H) 8.69 (d, J=2.64 Hz, 1H) 9.17 (s, 1H).

98B

(R)-Methyl3-(2-(isopropylthio)-5-nitrophenyl)-3-((S)-4-methylphenylsulfinamido)propanoate

To a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 0.82 mL)in Et₂O at −78° C. was added methyl acetate (0.065 mL, 0.82 mmol). Afterstirring for 30 min at −78° C., a solution of 98A (150 mg, 0.41 mmol) ina mixture of Et₂O (1.0 m) and THF (1.0 mL) was slowly added. The mixturewas stirred for 30 min before it was quenched by addition of sat.ammonium chloride solution at −78° C. After it warmed up to rt, it wasdiluted with EtOAc, washed with brine, dried over Na₂SO₄. After columnpurification (EtOAc:hexanes=1:2), 98B (318 mg, 90% yield) was obtainedas viscous oil). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.42 (m, 6H) 2.42 (s, 3H)2.84-2.93 (m, 2H) 3.63 (s, 3H) 5.34 (s, 1H) 7.32 (d, J=7.91 Hz, 2H) 7.40(d, J=7.91 Hz, 1H) 7.46 (d, J=8.79 Hz, 1H) 7.60 (d, J=7.91 Hz, 2H) 8.10(dd, J=8.57, 2.42 Hz, 1H) 8.36 (d, J=2.64 Hz, 1H); LC MS 437 (M+H).

98C (R)-Methyl 3-amino-3-(2-(isopropylthio)-5-nitrophenyl)propanoate

A solution of 98B (550 mg, 1.3 mmol) in methanol (5.0 mL) was treatedwith TFA (0.28 mL, 3.78 mmol) at 0° C. for 2.0 h and at rt for 1.0 h.After removal of solvent, the crude was diluted with diethyl ether andwashed with 3.0 N HCl (3×4.0 mL). The ether layer was discarded and theaqueous was made basic by addition of 1.0 N NaOH (15 mL). The aqueouswas extracted with EtOAc and dried over Na₂SO₄. After evaporation ofsolvent 98C (220 mg, 58% yield) was obtained as viscous oil. It was usedfor next step without further purification. ¹H NMR (400 MHz, CDCl₃) δppm 1.39 (m, 6H) 2.59 (dd, J=16.70, 9.67 Hz, 1H) 2.71-2.81 (m, 1H)3.56-3.64 (m, 1H) 3.71 (s, 3H) 4.06-4.17 (m, 1H) 4.87 (dd, J=9.67, 3.08Hz, 1H) 7.36 (d, J=8.79 Hz, 1H) 8.05 (dd, J=8.79, 2.20 Hz, 1H) 8.46 (d,J=2.64 Hz, 1H).

98D

(R)-Methyl3-(tert-butoxycarbonyl)-3-(2-(isopropylthio)-5-nitrophenyl)propanoate

A solution of 98C (220 mg, 0.74 mmol) in THF (2.0 mL) was treated with asolution of di-tert-butyldicarbonate (1.0 M in THF, 1.3 mL, 1.3 mmol)and triethyl amine (0.13 ml, 0.93 mmol) at rt for 4.0 h. It was dilutedwith EtOAc, washed with 1.0 N HCl and brine, dried over Na₂SO₄. Afterevaporation of solvent, 98D (230 mg, 82% yield) was obtained as viscousoil used for the next step without further purification. ¹H NMR (400MHz, CDCl₃) δ ppm 1.44 (m, 15H) 2.84 (d, J=3.95 Hz, 2H) 3.58-3.67 (m,4H) 5.39 (s, 1H) 5.91 (d, J=1.76 Hz, 1H) 7.38 (d, J=8.79 Hz, 1H) 8.04(dd, J=8.57, 2.42 Hz, 1H) 8.19 (d, J=2.64 Hz, 1H).

98E (R)-Methyl3-(tert-butoxycarbonyl)-3-(2-(isopropylthio)-5-(methoxycarbonyl)phenyl)propanoate

A solution of 98D (230 mg, 0.63 mmol) in methanol was hydrogenated witha hydrogen balloon over 10% Pd/C (50 mg) for 2.0 h. After evaporation ofsolvent, the crude was dissolved in pyridine (2.0 mL) and treated withmethyl chloroformate (0.085 mL, 1.1 mmol) at 0° C. for 30 min and thenat rt for 2.0 h. It was diluted with EtOAc, washed with 5.0 N HCl, brineand dried over Na₂SO₄. After evaporation of solvent and columnpurification (EtOAc:hexanes=1:2), 98E (210 mg, 80% yield) was obtainedas a viscous oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.25-1.31 (m, 6H) 1.41(s, 9H) 2.85 (d, J=4.83 Hz, 2H) 3.28-3.38 (m, 1H) 3.61 (s, 3H) 3.77 (s,3H) 6.67 (s, 1H) 7.24 (s, 1H) 7.42 (s, 2H).

98F (R)-Methyl3-amino-3-(2-(isopropylthio)-5-(methoxycarbonyl)phenyl)propanoate

A solution of 98E (210 mg, 0.49 mmol) in EtOAc (2.5 mL) was treated with4.0 N HCl in dioxane (2.5 mL, 10 mmol) at rt for 4.0 h. Afterevaporation of solvent, 98F was obtained as white solid used for nextstep without further purification. ¹H NMR (400 MHz, Methanol-d₄) δ ppm1.18 (d, J=6.59 Hz, 6H) 2.93 (dd, J=16.92, 5.49 Hz, 1H) 3.11 (dd,J=17.14, 8.35 Hz, 1H) 3.18-3.28 (m, 1H) 3.64 (s, 3H) 3.66 (s, 3H) 5.42(dd, J=8.35, 5.27 Hz, 1H) 7.48 (s, 2H) 7.63 (s, 1H); LC MS 327 (M+H).

98G

Example 98 was prepared according to the general coupling-deprotectionusing 73A and 98F. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.07-1.14 (m, 6H)1.18-1.24 (m, 3H) 2.58-2.80 (m, 2H) 3.22-3.30 (m, 1H) 3.32 and 3.53 (s,3H) 3.57 and 3.64 (s, 3H) 3.74-3.93 (m, 2H) 5.24 and 5.35 (s, 1H)5.88-6.02 (m, 1H) 6.55 (dd, J=23.95, 1.98 Hz, 1H) 6.66-7.38 (m, 8H)7.90-8.09 (m, 1H) 8.80 (dd, J=23.29, 8.35 Hz, 1H); LC MS 664 (M+H).

Example 992-(1-Amino-isoquinolin-6-ylamino)-N-[(R)-1-(2-ethanesulfonyl-phenyl)-ethyl]-2-(3-ethoxy-4-isobutyl-phenyl)-acetamidetrifluoroacetic acid salt

99A 2-((R)-1-Pivalamidoethyl)benzenesulfinic acid

99A was prepared in 45% yield according to a literature procedure (J.Chem. Soc. Perkin Trans. 1993, 1585). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.13(s, 9H) 1.54 (d, J=6.59 Hz, 3H) 6.09-6.16 (m, 1H) 7.34 (t, J=7.69 Hz,2H) 7.43-7.49 (m, 1H) 7.57 (d, J=7.47 Hz, 1H).

99B Sodium 2-((R)-1-pivalamidoethyl)benzenesulfinate

To a solution of 99A (160 mg, 0.59 mmol) in MeOH (4.0 mL) was added 1.0N NaOH (0.65 mL, 0.65 mmol). The mixture was stirred at rt for 2.0 h.MeOH was removed and the residue was suspended in H₂O and lyophilized togive 99B as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (s, 9H)1.45 (d, J=7.03 Hz, 3H) 5.27-5.35 (m, 1H) 7.14-7.24 (m, 3H) 7.73 (d,J=7.47 Hz, 1H) 8.98 (d, J=8.35 Hz, 1H).

99C (R)-N-(1-(2-(Ethylsulfonyl)phenyl)ethyl)pivalamide

A mixture of 99B (150 mg, 0.51 mmol) and ethyl iodide (0.056 mL, 0.69mmol) in DMF (2.0 mL) was heated at 40° C. for 1.0 h. It was dilutedwith EtOAc, washed with brine and dried over Na₂SO₄. After evap[orationof solvent, 99C (120 mg) was obtained and used for next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.15 (s, 9H)1.25-1.30 (m, 3H) 1.41-1.44 (m, 3H) 3.53-3.63 (m, 2H) 5.43-5.52 (m, 1H)6.38 (d, J=5.71 Hz, 1H) 7.30-7.36 (m, 1H) 7.42-7.48 (m, 1H) 7.52 (d,J=7.47 Hz, 1H) 7.89 (d, J=6.59 Hz, 1H).

99D (R)-1-(2-(Ethylsulfonyl)phenyl)ethanamine

A mixture of 99C (120 mg) and conc. HCl (5.0 mL) was heated at 128° C.for 10 h. After evaporation of solvent, the crude was purified by a prepHPLC to give 99D (96 mg) as a TFA salt. ¹H NMR (400 MHz, Methanol-d₄) δppm 1.27 (t, J=7.25 Hz, 3H) 1.69 (d, J=7.03 Hz, 3H) 5.38 (q, J=6.88 Hz,1H) 7.68 (ddd, J=8.02, 5.38, 2.86 Hz, 1H) 7.83-7.88 (m, 2H) 8.06 (d,J=7.91 Hz, 1H); LC MS 214 (M+H).

99E

Example 99 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 99D. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.14(m, 12H) 3.49-4.50 (m, 5H), 5.07 and 5.09 (s, 1H), 6.60-8.07 (m, 11H)8.97-9.12 (m, 1H); LC MS 591 (M+H).

Example 100(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetylamino]-3-(2-isopropylsulfanyl-5-methoxycarbonylamino-phenyl)-propionicacid methyl ester trifluoroacetic acid salt

Example 100 was prepared according to the general coupling-deprotectionusing Intermediate 4 and 98F. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.20(m, 6H) 2.74 (d, J=4.83 Hz, 1H) 2.77 (m, 2H) 3.35 (m, 1H) 3.66 (s, 3H)3.79 (s, 3H) 3.82 (s, 3H) 4.99 (s, 1H) 5.98-6.02 (m, 1H) 6.59 (s, 1H)6.83 (d, J=7.47 Hz, 1H) 6.93 (d, J=7.91 Hz, 1H) 7.04-7.08 (m, 4H) 7.11(s, 1H) 7.16 (d, J=9.23 Hz, 1H) 7.29 (d, J=7.03 Hz, 1H) 7.33 (d, J=8.35Hz, 1H) 8.06 (d, J=9.23 Hz, 1H); LC MS 662 (M+H).

Example 1012-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isobutyl-phenyl)-N-(3-methyl-benzyl)-acetamidetrifluoroacetic acid salt

Example 101 was prepared according to the general coupling-deprotectionusing Intermediate 2 and commercial m-tolylmethanamine. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.18 (d, J=5.71 Hz, 6-H) 1.25 (t, J=7.03 Hz, 3H) 2.05(s, 3H) 3.87 (q, J=7.03 Hz, 2H) 4.14-4.36 (m, 2H) 4.36-4.48 (m, 1H) 4.94(s, 1H) 6.55 (d, J=1.76 Hz, 1H) 6.68 (d, J=7.03 Hz, 1H) 6.76 (s, 1H)6.79-6.91 (m, 3H) 6.93-7.01 (m, 3H) 7.07 (dd, J=9.23, 2.20 Hz, 1H) 7.21(d, J=7.03 Hz, 1H) 7.97 (d, J=9.23 Hz, 1H) 8.68 (t, J=6.15 Hz, 1H); LCMS 497 (M+H).

Example 102(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-phenyl)-acetylamino]-3-(2-isopropylsulfanyl-5-methoxycarbonylamino-phenyl)-propionicacid trifluoroacetic acid salt

Example 102 was prepared from Example 98 by hydrolysis of the methylester as described in procedure 5E. ¹H NMR (400 MHz, Methanol-d₄) δ ppm1.19 (m, 6H) 1.31 (m, 3H) 2.69-2.80 (m, 1H) 3.65 and 3.74 (s, 3H)3.83-3.94 (m, 2H) 5.38 and 5.46 (s, 1H) 6.00 (m, 1H) 6.64-7.41 (m, 9H)8.03-8.09 (m, 2H) LC MS650(M+H).

Example 103(R)-3-[(R)-2-(1-Amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetylamino]-3-(2-isopropylsulfanyl-5-methoxycarbonylamino-phenyl)-propionicacid trifluoroacetic acid salt

Example 103 was prepared from Example 100 by hydrolysis of the methylester as described in procedure 5E. The enantiomer was separated fromthe diastereomers by prep HPLC. ¹H NMR-(400 MHz, Methanol-d₄) δ ppm 1.20(m, 6H) 2.74 (m, 1H) 3.66 (s, 3H) 3.80 (s, 3H) 3.82 (s, 3H) 4.99 (s, 1H)6.00 (dd, J=9.67, 4.83 Hz, 1H) 6.59 (s, 1H) 6.83 (d, J=7.47 Hz, 1H) 6.93(d, J=7.91 Hz, 1H) 7.04-7.08 (m, 4H) 7.10-7.18 (m, 2H) 7.29 (d, J=7.03Hz, 1H) 7.33 (d, J=8.35 Hz, 1H) 8.02-8.08 (m, 2H); LCMS 648(M+H).

Example 1042-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-(3-fluoromethyl-benzyl)-acetamidetrifluoroacetic acid salt

104A 3-(Fluoromethyl)benzonitrile

To a solution of 3-hydroxybenzonitrile (133 mg, 1.0 mmol) indichloromethane (5.0 mL) was added (diethylamino)sulfur trifluoride(DAST, 0.26 mL, 2.0 mmol) at rt. After stirring for two hours, thereaction was quenched by 5 mL of saturated NaHCO₃ solution, andextracted by dichloromethane (2×5 mL). The combined organic layer waswashed by brine, dried over MgSO₄, and concentrated. The crude productwas purified by column chromatography to give 80 mg (59% yield)colorless liquid of 104A. ¹H NMR (400 MHz, CDCl₃) δ ppm 5.42 (d, J=47.02Hz, 2H) 7.53 (t, J=7.69 Hz, 1H) 7.59-7.63 (m, 1H) 7.64-7.70 (m, 2H).

104B (3-(Fluoromethyl)phenyl)methanamine

To 104A (110 mg, 0.82 mmol) in THF (2.5 mL) was added 1.0 M borane THFcomplex solution (2.4 mL, 2.4 mmol) at 0° C. The mixture was stirredfrom 0° C. to rt for 2 h before it was quenched by addition of 2.5 mL of1.0 N HCl solution and 2.5 mL of MeOH. The mixture was stirred at rtovernight, extracted by EtOAc, washed by saturated NaHCO₃ solution andbrine. The organic layer was dried by MgSO₄, and concentrated. The crudeproduct was purified by HPLC to give 76 mg (37% yield) white solid of104B as trifluoroacetic acid salt. ¹H NMR (400 MHz, Methanol-d₄) δ ppm4.01 (s, 2H) 5.28 (d, J=47.46 Hz, 2H) 7.24-7.49 (m, 4H).

104C

Example 104 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 104B. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.21(d, J=5.71 Hz, 6H) 1.27 (t, J=7.03 Hz, 3H) 3.87-3.94 (m, 2H) 4.24-4.31(m, 1H) 4.37-4.47 (m, 2H) 4.98 (s, 1H) 5.04 (s, 1H) 5.16 (s, 1H) 6.58(d, J=2.20 Hz, 1H) 6.71 (d, J=7.03 Hz, 1H) 6.86-6.89 (m, 1H) 6.97-7.00(m, 1H) 7.01 (s, 2H) 7.05-7.16 (m, 4H) 7.23 (d, J=7.47 Hz, 1H) 7.99 (d,J=9.23 Hz, 1H) 8.77 (t, J=6.15 Hz, 1H); LC MS 517 (M+H).

Example 1052-(1-Amino-isoquinolin-6-ylamino)-N-(2-cyclobutanesulfonyl-benzyl)-2-(5-ethoxy-2-fluoro-4-methoxy-phenyl)-N-methyl-acetamidetrifluoroacetic acid salt

105A 4-Fluoro-2-methoxyphenyl acetate

To a solution of 4-fluoro-2-methoxyphenol (569 mg, 4.0 mmol) andpyridine (0.56 mL, 7.0 mmol) in CH₂Cl₂ (8.0 mL) at 0° C. was addedacetyl chloride (0.33 mL, 4.6 mmol). The mixture was stirred at rt for2.0 h and then diluted with EtOAc and washed with 4.0 N HCl. The organiclayer was washed with brine and dried over Na₂SO₄. After evaporation ofsolvent, 105A (680 mg, 92% yield) was obtained as a solid used for thenext step without further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm2.29 (s, 3H) 3.79 (s, 3H) 6.62 (m, 1H) 6.68 (dd, J=10.33, 2.86 Hz, 1H)6.95 (dd, J=8.79, 5.71 Hz, 1H).

105B 4-Fluoro-5-iodo-2-methoxyphenyl acetate

To a solution of 105A (850 mg, 4.6 mmol) in CH₂Cl₂ (5.0 mL) was addedICl (1.0 M in CH₂Cl₂, 10.2 mL, 10.2 mmol). The mixture was stirred at50° C. for 4 h and then at rt for 18 h. The reaction was quenched by asat. solution of NaHCO₃. After extraction with CH₂Cl₂, the organic layerwas washed with a solution of Na₂S₂O₃, brine and dried over Na₂SO₄.After evaporation of solvent, the crude was purified by columnchromatography (EtOAc:hexanes=1:4) to give 105B (1.22 g, 80% yield) as asolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.29 (s, 3H) 3.81 (s, 3H) 6.73 (d,J=9.23 Hz, 1H) 7.35 (d, J=6.59 Hz, 1H).

105C 4-Fluoro-5-iodo-2-methoxyphenol

To a solution of 105B (680 mg, 2.19 mmol) in THF (3.0 mL) and MeOH (1.0mL) was added 1.0 N NaOH (2.74 mL, 2.74 mmol). The reaction was stirredat rt for 2.0 h before it was acidified by addition of 5% citric acid.The mixture was extracted with EtOAc, washed with brine and dried overNa₂SO₄. After evaporation of solvent, 105C (586 mg, 100% yield) wasobtained as a solid and used for next step without further purification.¹H NMR (400 MHz, CDCl₃) δ ppm 3.85 (s, 3H) 6.62 (d, J=8.79 Hz, 1H) 7.21(d, J=6.15 Hz, 1H).

105D 1-Ethoxy-4-fluoro-5-iodo-2-methoxybenzene

A mixture of 105C (580 mg, 2.16 mmol), ethyl iodide (0.23 mL, 2.92 mmol)and K₂CO₃ (598 mg, 4.32 mmol) in DMF (5.0 mL) was heated at 40° C. for3.0 h. It was diluted with diethyl ether, washed with brine and driedover Na₂SO₄. After evaporation of solvent, the crude was purified by acolumn chromatography (EtOAc:hexanes=1:5) to give 105D (540 mg, 85%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.42 (t, J=7.03Hz, 3H) 3.82 (s, 3H) 4.01 (q, J=7.03 Hz, 2H) 6.64 (d, J=9.23 Hz, 1H)7.09 (d, J=6.15 Hz, 1H).

105E 5-Ethoxy-2-fluoro-4-methoxyphenylboronic acid

To a solution of 105D (324 mg, 1.1 mmol) in THF (5 mL) at −78° C.,n-BuLi (1.6 M in hexanes, 1.40 mL, 2.2 mmol) was slowly added. Thereaction mixture was stirred at −78° C. for 20 min, followed by additionof trimethyl borate (0.31 mL, 2.8 mmol). The mixture was stirred at −78°C. for 3.0 h and then warm up to rt over 18 h. It was quenched byaddition of 1.0 N HCl (2.0 mL). After extraction with EtOAc, washingwith a solution of Na₂S₂O₃, brine and drying over Na₂SO₄, the crude waspurified by chromatography to give 105E (210 mg, 80% yield) as a whitesolid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.36 (t, J=6.81 Hz, 3H) 3.86(s, 3H) 4.00 (q, J=7.03 Hz, 2H) 6.72 (d, J=10.11 Hz, 1H) 6.89 (d, J=5.27Hz, 1H).

105F2-(1-di-tert-Butoxycarbonylaminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-4-methoxyphenyl)aceticacid

A mixture of 105E (118 mg, 0.55 mmol), Intermediate 1 (180 mg, 0.5 mmol)and glyoxylic acid monohydrate (51 mg, 0.55 mmol) in acetonitrile (1.3mL) and DMF (0.13 mL) was heated at 85° C. for 25 min in a microwaveoven. After removing solvent, the crude was purified by chromatographyeluting with CH₂Cl₂:MeOH=100:20 to give 105F (190 mg, 65% yield) as ayellow solid. ¹H NMR (400 MHz, acetonitrile-d₃) δ ppm 1.91 (m, 21H) 3.76(s, 3H) 3.92 (dd, J=10.11, 7.03 Hz, 2H) 5.45 (s, 1H) 6.70 (d, J=2.20 Hz,1H) 6.79 (d, J=11.86 Hz, 1H) 6.92 (d, J=7.03 Hz, 1H) 7.17 (dd, J=9.01,2.42 Hz, 1H) 7.38 (d, J=5.27 Hz, 1H) 7.63 (d, J=8.79 Hz, 1H) 8.08 (d,J=5.71 Hz, 1H); LC MS 586 (M+H).

105G

Example 105 was prepared according to the general coupling-deprotectionusing 105F and Intermediate 12. ¹H NMR (400 MHz, Methanol-d₄) δ ppm amixture of two rotomers: 1.28 (m, 3H) 1.91-2.70 (m, 5H) 2.92 and 3.06(s, 3H) 3.59 and 3.76 (s, 3H) 3.88-4.10 (m, 3H) 5.08 and 5.12 (s, 1H)6.74-7.40 (m, 9H), 7.83-8.00 (m, 2H); LC MS 607 (M+H).

Example 1062-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-(3-isopropylsulfanyl-pyridin-2-ylmethyl)-acetamidetrifluoroacetic acid salt

Example 106 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 72D. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.15(d, J=6.59 Hz, 6H) 1.20 (d, J=5.71 Hz, 6H) 1.28 (t, J=6.81 Hz, 3H)3.30-3.39 (m, 1H) 3.95 (q, J=7.03 Hz, 2H) 4.38-4.46 (m, 1H) 4.55 (d,J=18.02 Hz, 1H) 5.07 (s, 1H) 6.64 (d, J=2.20 Hz, 1H) 6.77 (d, J=7.03 Hz,1H) 6.86 (d, J=8.35 Hz, 1H) 6.98 (dd, J=8.35, 2.20 Hz, 1H) 7.06 (d,J=2.20 Hz, 1H) 7.11 (dd, J=9.23, 2.20 Hz, 1H) 7.21-7.26 (m, 2H) 7.79 (d,J=7.91 Hz, 1H) 7.99 (d, J=9.23 Hz, 1H) 8.24 (d, J=4.83 Hz, 1H); LC MS546 (M+H).

Example 1072-(1-Amino-isoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-phenyl)-N-(3-isopropylsulfanyl-pyridin-2-ylmethyl)-acetamidetrifluoroacetic acid salt

Example 107 was prepared according to the general coupling-deprotectionusing 73A and 72D. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.17 (d, J=7.03Hz, 6H) 1.25 (t, J=7.03 Hz, 3H) 3.32-3.42 (m, 1H) 3.88 (q, J=6.74 Hz,2H) 4.49-4.57 (m, 1H) 4.59-4.65 (m, 1H) 5.46 (s, 1H) 6.70 (d, J=2.20 Hz,1H) 6.77-6.83 (m, 2H) 6.96-7.03 (m, 2H) 7.12 (dd, J=9.23, 2.64 Hz, 1H)7.21-7.27 (m, 2H) 7.80 (d, J=6.59 Hz, 1H) 8.01 (d, J=9.23 Hz, 1H) 8.25(dd, J=4.83, 1.76 Hz, 1H); LC MS 506(M+H).

Example 108N-(3-Acetylamino-benzyl)-2-(4-aminomethyl-phenylamino)-2-(4-chloro-3-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

108A2-(4-((tert-butoxycarbonyl)methyl)phenylamino)-2-(4-chloro-3-methoxyphenyl)aceticacid

A mixture of 79A (102 mg, 0.55 mmol), (4-amino-benzyl)-carbamic acidtert-butyl ester (111 mg, 0.5 mmol) and glyoxylic acid monohydrate (51mg, 0.55 mmol) in toluene (5 mL) and MeOH (0.4 mL) was heated at 55° C.for 5.0 h. After removing solvent, the crude was purified bychromatography eluting with CH₂Cl₂:MeOH=100:10 to give 108A (39 mg, 18%yield) as a yellow solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.33 (s,9H) 3.75 (s, 3H) 3.97 (s, 2H) 5.02 (s, 1H) 6.58 (d, J=8.56 Hz, 2H) 6.96(m, 3H) 7.10 (d, J=1.96 Hz, 1H) 7.22 (d, J=8.07 Hz, 1H).

108B

Example 108 was prepared according to the general coupling-deprotectionusing 108A and commercial N-(3-(aminomethyl)phenyl)acetamide HCl salt.¹H NMR (400 MHz, Methanol-d₄) δ ppm 2.02 (s, 3H) 3.71 (s, 3H) 3.85 (s,2H) 4.26 (d, J=5.62 Hz, 2H) 4.87 (s, 1H) 6.62 (d, J=8.56 Hz, 2H) 6.80(d, J=7.34 Hz, 1H) 6.96 (dd, J=8.07, 1.96 Hz, 1H) 7.09 (m, 4H) 7.23 (d,J=8.07 Hz, 2H) 7.34 (s, 1H) 8.68 (m, 1H); LC MS 467 (M+H).

Example 1092-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-pyridin-2-ylmethyl-acetamidetrifluoroacetic acid salt

Example 109 was prepared according to the general coupling-deprotectionusing Intermediate 2 and commercial pyridin-2-ylmethanamine HCl salt. ¹HNMR (400 MHz, Methanol-d₄) δ ppm 1.23 (d, J=6.11 Hz, 6H) 1.30 (t, J=7.09Hz, 3H) 3.97 (q, J=7.09 Hz, 2H) 4.48 (m, 3H) 5.09 (s, 1H) 6.65 (d,J=2.20 Hz, 1H) 6.79 (d, J=7.09 Hz, 1H) 6.91 (d, J=8.31 Hz, 1H) 7.03 (m,1H) 7.07 (d, J=2.20 Hz, 1H) 7.14 (m, 2H) 7.30 (m, 2H) 7.73 (m, 1H) 8.02(d, J=9.29 Hz, 1H) 8.42 (d, J=4.40 Hz, 1H); LC MS 486 (M+H).

Example 110(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetylamino]-3-(3-amino-phenyl)-propionicacid trifluoroacetic acid salt

Example 110 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 60B followed by hydrolysis of the ethyl esteras described in procedure 5E. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.33(m, 9H) 2.86 (m, 2H) 3.98 (m, 2H) 4.51 (m, 1H) 5.07 (s, 1H) 5.36 (m, 1H)6.64 (d, J=17.36 Hz, 1H) 6.87 (m, 2H) 7.04 (m, 3H) 7.18 (m, 3H) 7.33 (m,1H) 7.48 (d, J=4.89 Hz, 1H) 8.06 (m, 1H) 8.97 (t, J=8.19 Hz, 1H); LC MS558 (M+H).

Example 111(R)-3-(3-Acetylamino-phenyl)-3-[2-(1-amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetylamino]-propionicacid trifluoroacetic acid salt

Example 111 was prepared according to the general coupling-deprotectionusing Intermediate 4 and 60E followed by hydrolysis of the methyl esteras in procedure 5E. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 2.74 (m, 2H)3.71 (m, 6H) 4.97 (m, 1H) 5.27 (m, J=9.41, 5.01 Hz, 1H) 6.50 (m, 1H)6.70 (m, 2H) 6.85 (d, J=8.31 Hz, 1H) 7.01 (m, 4H) 7.24 (m, 3H) 7.96 (m,1H) 8.74 (d, J=8.31 Hz, 1H); LC MS 558 (M+H).

Example 112(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetylamino]-3-(2-fluoro-phenyl)-propionicacid methyl ester trifluoroacetic acid salt

Example 112 was prepared according to the general coupling-deprotectionusing Intermediate 2 and commercial (R)-methyl3-amino-3-(2-fluorophenyl)propanoate HCl salt. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.27 (m, 9H) 2.77 (m, 2H) 3.37 (m, 3H) 3.94 (m, 2H)4.45 (m, 1H) 4.99 (s, 1H) 5.52 (m, J=4.16 Hz, 1H) 6.54 (s, 1H) 6.82 (m,3H) 7.03 (m, 5H) 7.28 (m, 2H) 7.99 (t, J=9.66 Hz, 1H) 8.79 (m, 1H); LCMS 575 (M+H).

Example 113(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetylamino]-3-(2-fluoro-phenyl)-propionicacid methyl ester trifluoroacetic acid salt

Example 113 was prepared according to the general coupling-deprotectionusing Intermediate 4 and commercial (R)-methyl3-amino-3-(2-fluorophenyl)propanoate HCl salt. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 2.84 (m, 2H) 3.77 (m, 9H) 5.08 (d, J=2.93 Hz, 1H)5.61 (dd, J=9.29, 5.38 Hz, 1H) 6.64 (dd, J=17.36, 2.20 Hz, 1H) 6.90 (m,4H) 7.13 (m, 4H) 7.37 (m, 2H) 8.07 (dd, J=10.52, 9.54 Hz, 1H); LC MS 533(M+H).

Example 114(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetylamino]-3-(2-fluoro-phenyl)-propionicacid trifluoroacetic acid salt

Example 114 was prepared by hydrolysis of Example 113 using LiOH inaqueous THF. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 2.73 (m, 2H) 3.73 (m,6H) 5.02 (d, J=12.72 Hz, 1H) 5.52 (m, 1H) 6.56 (m, 1H) 6.82 (m, 4H) 7.05(m, 4H) 7.25 (m, 2H) 7.98 (t, J=9.66 Hz, 1H) 8.79 (d, J=36.44 Hz, 1H);LC MS 519 (M+H).

Example 115(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetylamino]-3-(2-fluoro-phenyl)-propionicacid trifluoroacetic acid salt

Example 115 was prepared by hydrolysis of Example 112 using LiOH inaqueous THF. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.25 (m, 9H) 2.71 (m,2H) 3.90 (m, 2H) 4.44 (m, 1H) 5.00 (d, J=6.85 Hz, 1H) 5.51 (m, 1H) 6.56(m, 1H) 6.82 (m, 4H) 7.03 (m, 4H) 7.25 (m, 2H) 7.97 (dd, J=9.29, 5.62Hz, 1H); LC MS 561 (M+H).

Example 116(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetylamino]-3-[2-(propane-2-sulfonyl)-phenyl]-propionicacid methyl ester trifluoroacetic acid salt

116A 2-(Isopropylthio)benzaldehyde

To 2-fluorobenzaldehyde (2.0 g, 16.1 mmol) and 2-thiopropane (1.65 mL,17.7 mmol) in DMF (6 mL) was added potassium carbonate (2.45 g, 17.7mmol). The reaction mixture was stirred overnight at 70° C. Aftercooling, the crude reaction mixture was filtered over Celite® and washedwith ethyl acetate. The combined filtrate and washings was concentrated.The residue was redissolved in ethyl acetate and washed with water (3×)and then dried over sodium sulfate. The crude mixture was purified byflash column chromatography to give 1.7 g of yellow oil product 116A(60% total yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.32 (d, J=6.85 Hz, 6H)3.41 (m, 1H) 7.35 (d, J=4.40 Hz, 1H) 7.51 (m, 2H) 7.87 (d, J=7.34 Hz,1H) 10.53 (s, 1H).

116B tert-Butyl 3-(2-(isopropylthio)phenyl)acrylate

To tert-butyldiethylphosphonoacetate (0.52 mL, 2.2 mmol) in THF (1.5 mL)at 0° C. was added sodium hydride (95%, 0.056 g, 2.2 mmol) and stirredfor 30 min. To this mixture was added 116A (0.2 g, 1.1 mmol) in THF (1.5mL) and allowed to warm to rt and stirred overnight. The reaction wasquenched with sat. ammonium chloride and then extracted with ether,washed with brine and dried over sodium sulfate. The solvent was removedand the crude product was purified by flash column chromatography togive 0.28 g of colorless oil 116B (92%). ¹H NMR (400 MHz, CDCl₃) δ ppm1.20 (d, J=6.85 Hz, 6H) 1.47 (s, 9H) 3.22 (m, 1H) 6.23 (d, J=15.89 Hz,1H) 7.21 (m, 2H) 7.42 (dd, J=7.58, 1.47 Hz, 1H) 7.52 (dd, J=7.46, 1.59Hz, 1H) 8.20 (d, J=15.90 Hz, 1H).

116C (R)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-3-(2-(isopropylthio)phenyl)propanoate

To (S)-(−)-N-benzyl-1-phenylethylamine (0.4 mL, 1.9 mmol) in THF at −78°C. was added n-butyl lithium (1.18 mL, 1.6 M in hexanes, 1.9 mmol)dropwise. The reaction was stirred at −78° C. for 30 min., then 116B(0.28 g, 1.0 mmol) in THF was added slowly. The reaction was stirred at−78° C. for 2 h. The reaction was quenched with sat. ammonium chlorideand stirred overnight at rt. The aqueous layer was extracted with ethylacetate (2×). The combined organic extracts was washed with brine anddried over sodium sulfate. The solvent was removed and the crude productwas purified by flash column chromatography to give 0.41 g of colorlessoil 116C (84%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.10 (m, 9H) 1.17 (m, 6H)1.28 (d, J=6.85 Hz, 3H) 2.26 (dd, J=14.18, 10.03 Hz, 1H) 2.57 (dd,J=14.06, 5.75 Hz, 1H) 3.40 (m, 1H) 3.67 (s, 2H) 3.86 (d, J=6.85 Hz, 1H)4.95 (dd, J=10.03, 5.62 Hz, 1H) 7.12 (m, 10H) 7.35 (m, 3H) 7.52 (m, 1H).

116D (R)-tert-butyl3-(benzyl((S)-1-phenylethyl)amino)-3-(2-(isopropylsulfonyl)phenyl)propanoate

To 116C (0.14 g, 0.28 mmol) in methanol (2 mL) was added Oxone® (0.53 g,0.86 mmol) in water (1.5 mL) and stirred at rt overnight. The reactionwas quenched with 5% NaHSO₃ and then neutralized with 1 M NaOH. Theorganic solvent was evaporated and the aqueous layer was extracted withdichloromethane (3×). The combined extracts were washed with brine anddried over sodium sulfate. The solvent was removed and the crude residuewas purified by flash column chromatography to give 0.13 g of whitesolid product 116D (87% yield). ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.06(d, J=6.60 Hz, 3H) 1.27 (d, J=11.74 Hz, 12H) 1.45 (d, J=6.85 Hz, 3H)2.24 (dd, J=16.14, 3.91 Hz, 1H) 2.60 (m, 1H) 3.44 (m, 1H) 3.79 (s, 2H)3.96 (m, 1H) 5.50 (m, 1H) 7.10 (m, 6H) 7.21 (m, 4H) 7.43 (t, J=7.21 Hz,2H) 7.65 (t, J=7.09 Hz, 1H) 7.91 (dd, J=12.72, 8.07 Hz, 2H).

116E (R)-tert-Butyl-3-amino-3-(2-(isopropylsulfonyl)phenyl)propanoate

To 116D (0.12 g, 0.23 mmol) in methanol (10 mL) and acetic acid (0.1 mL)under nitrogen was added 20% Pd(OH)₂ (0.12 g) and then a balloon filledwith hydrogen gas was introduced. The reaction was stirred for 4 h atrt. The catalyst was filtered off and the filtrate was concentrated. Theresidue was dissolved in methanol and a base resin (Supelco Diaion WA21Jresin, 0.5 g) was added. The mixture was stirred for 1 h and thenfiltered and concentrated to give 0.07 g (89% yield) of 116E. ¹H NMR(400 MHz, Methanol-d₄) δ ppm 1.17 (m, 6H) 1.27 (m, 9H) 2.73 (m, 2H) 3.60(m, 1H) 5.01 (t, J=7.34 Hz, 1H) 7.45 (m, 1H) 7.69 (m, 2H) 7.88 (dd,J=7.95, 1.10 Hz, 1H).

116F

Example 116 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 116E. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.22(m, 15H) 2.75 (m, 2H) 3.28 (m, 3H) 3.87 (dd, J=22.01, 6.85 Hz, 1H) 3.99(q, J=7.09 Hz, 1H) 4.11 (dd, J=8.31, 6.85 Hz, 1H) 4.47 (m, 1H) 4.98 (d,J=7.09 Hz, 1H) 5.91 (m, 1H) 6.58 (dd, J=34.24, 2.20 Hz, 1H) 6.93 (m, 5H)7.09 (m, 1H) 7.26 (m, 1H) 7.41 (m, 1H) 7.70 (dd, J=18.83, 0.98 Hz, 1H)7.82 (m, 1H) 8.01 (dd, J=19.56, 9.05 Hz, 1H) 9.05 (dd, J=25.80, 7.21 Hz,1H); LC MS 663 (M+H).

Example 117(R)-3-[2-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetylamino]-3-[2-(propane-2-sulfonyl)-phenyl]-propionicacid trifluoroacetic acid salt

Example 117 was prepared by hydrolysis of Example 116 in a proceduresimilar to that of procedure 5E. ¹H NMR (400 MHz, Methanol-d₄) δ ppm1.24 (m, 15H) 2.72 (m, 2H) 3.90 (m, 2H) 4.13 (m, 1H) 4.46 (m, 1H) 5.01(d, J=21.27 Hz, 1H) 5.87 (m, 1H) 6.59 (dd, J=23.48, 2.20 Hz, 1H) 6.92(m, 5H) 7.09 (m, 1H) 7.25 (m, 1H) 7.40 (m, 1H) 7.68 (m, 1H) 7.82 (m, 1H)8.00 (dd, J=18.71, 9.17 Hz, 1H) 9.09 (dd, J=23.48, 6.85 Hz, 1H); LC MS649 (M+H).

Example 118{(3-Acetylamino-benzyl)-[2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetyl]-amino}-aceticacid ethyl ester trifluoroacetic acid salt

118A Ethyl 2-(3-acetamidobenzylamino)acetate

To 3-acetamide benzylamine (0.15 g, 0.75 mmol) in DMF was addedpotassium carbonate (0.52 g, 3.75 mmol) and ethyl 2-bromoacetate (0.086mL, 0.78 mmol). The reaction mixture was stirred for 90 min at rt. Thereaction was diluted in ethyl acetate and washed with water (3×) andthen dried over sodium sulfate. The crude mixture was purified by flashcolumn chromatography to give 0.06 g of 118A (32% total yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.25 (t, J=7.21 Hz, 3H) 2.11 (s, 3H) 3.34 (d,J=4.65 Hz, 2H) 3.74 (s, 2H) 4.17 (q, J=7.09 Hz, 2H) 7.07 (d, J=7.83 Hz,1H) 7.26 (t, J=7.83 Hz, 1H) 7.46 (d, J=8.07 Hz, 1H) 7.50 (s, 1H).

118B

Example 118 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 118A. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.24(m, 12H) 2.03 (d, J=3.91 Hz, 3H) 4.01 (m, 6H) 4.52 (m, 3H) 5.48 (d,J=61.13 Hz, 1H) 6.88 (m, 7-H) 7.23 (m, 4H) 7.98 (m, 1H) 9.73 (d, J=11.25Hz, 1H); LC MS 628 (M+H).

Example 119{(3-Acetylamino-benzyl)-[2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetyl]-amino}-aceticacid trifluoroacetic acid salt

Example 119 was prepared by hydrolysis of Example 118 in a proceduresimilar to that of procedure 5E. ¹H NMR (400 MHz, Methanol-d₄) δ ppm1.27 (m, 9H) 2.03 (d, J=1.47 Hz, 3H) 3.98 (m, 5H) 4.44 (m, 2H) 5.44 (d,J=81.92 Hz, 1H) 6.89 (m, 7H) 7.23 (m, 4H) 7.97 (m, 1H); LC MS 600 (M+H).

Example 1202-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-{1-[2-(propane-2-sulfonyl)-phenyl]-ethyl}-acetamidetrifluoroacetic acid salt

120A 1-(2-(Isopropylthio)phenyl)ethanone

To 1-(2-fluorophenyl)ethanone (1.0 g, 7.2 mmol) and 2-thiopropane (1.3mL, 14.4 mmol) in DMF (4 mL) was added potassium carbonate (2.0 g, 14.4mmol). The reaction mixture was stirred overnight at 50° C. Aftercooling, the crude reaction mixture was diluted in ethyl acetate andwashed with water (3×) and then dried over sodium sulfate. The solventwas removed and the residue dried under high vacuum to give 1.4 gproduct 120A (>99% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.29 (dd,J=15.90, 6.60 Hz, 6H) 2.59 (s, 3H) 3.44 (m, 1H) 7.19 (m, 1H) 7.40 (m,2H) 7.64 (dd, J=7.70, 1.34 Hz, 1H).

120B 1-(2-(Isopropylsulfonyl)phenyl)ethanone

To 120A (0.5 g, 2.6 mmol) in methanol (5 mL) was added Oxone® (4.7 g,7.7 mmol) in water (5 mL) and stirred at room temperature for 3 h. Thereaction was quenched with 5% NaHSO₃ and then neutralized with 1 M NaOH.The organic solvent was evaporated and the aqueous layer was extractedwith dichloromethane (3×). The combined extracts were washed with brineand dried over sodium sulfate. The solvent was removed and the residuedried under high vacuum to give 0.45 g of 120B (78% yield). ¹H NMR (400MHz, CDCl₃) δ ppm 1.28 (d, J=6.85 Hz, 6H) 2.62 (s, 3H) 3.59 (m, 1H) 7.40(dd, J=7.58, 0.98 Hz, 1H) 7.57 (m, 1H) 7.66 (m, 1H) 7.95 (m, 1H).

120C 1-(2-(Isopropylsulfonyl)phenyl)ethanol

To 120B (0.09 g, 0.38 mmol) in methanol (2 mL) was added sodiumborohydride (0.07 g, 1.9 mmol). The reaction was quenched with waterafter 10 min of stirring at rt. The product was extracted with ethylacetate (3×) and then dried over sodium sulfate. The solvent was removedand place under high vacuum to give 0.08 g of 120C (90% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.11 (d, J=6.85 Hz, 3H) 1.29 (d, J=6.85 Hz, 3H)1.40 (m, 3H) 3.35 (m, 1H) 5.57 (q, J=6.20 Hz, 1H) 7.43 (m, 1H) 7.67 (m,1H) 7.83 (m, 2H).

120D 1-(2-(Isopropylsulfonyl)phenyl)ethyl diphenyl phosphate

To 120C (0.14 g, 0.61 mmol) in toluene was added diphenylphosphorylazide (0.25 g, 0.92 mmol) and the reaction was cooled to 0° C.1,8-Diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.92 mmol) was added andthe reaction was allowed to warm to rt and stirred for 2 h. The reactionwas quenched with water and then 10% citric acid. The aqueous layer wasextracted with ethyl acetate (3×) and the combined extracts were washedwith brine and dried over sodium sulfate. The solvent was removed andthe crude product was purified by flash column chromatography to give0.1 g of 120D. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.95 (d, J=6.60 Hz, 3H)1.27 (d, J=6.85 Hz, 3H) 1.57 (dd, J=6.24, 1.10 Hz, 3H) 3.47 (m, 1H) 6.44(m, 1H) 6.98 (m, 2H) 7.17 (m, 6H) 7.35 (t, J=7.95 Hz, 2H) 7.49 (m, 1H)7.64 (m, 1H) 7.70 (m, 1H) 7.81 (dd, J=8.07, 1.22 Hz, 1H).

120E 1-(1-Azidoethyl)-2-(isopropylsulfonyl)benzene

To 120D (0.11 g, 0.22 mmol) in DMF (10 mL) was added sodium azide (0.049g, 0.75 mmol). The reaction was stirred for 24 h at 60° C. Aftercooling, the crude reaction mixture was diluted in ethyl acetate andwashed with water (3×) and then dried over sodium sulfate. The solventwas removed and the residue was purified by flash column chromatographyto give 0.031 g of 120E (56% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.17(d, J=6.60 Hz, 3H) 1.26 (d, J=6.85 Hz, 3H) 1.49 (d, J=6.60 Hz, 3H) 3.32(m, 1H) 5.67 (q, J=6.68 Hz, 1H) 7.52 (m, 1H) 7.74 (m, 2H) 7.92 (d,J=7.83 Hz, 1H).

120F 1-(2-(Isopropylsulfonyl)phenyl)ethanamine hydrochloride

To 120E (0.031 g, 0.12 mmol) in methanol (5 mL) and hydrochloric acid(0.05 mL) under nitrogen was added 10% Pd/C (0.02 g) and then a balloonfilled with hydrogen gas was introduced. The reaction was stirred for 1h at rt. The catalyst was filtered off and washed with methanol. Thecombined filtrate and washings were concentrated and dried under highvacuum to give 0.03 g of 120F (>99%). ¹H NMR (400 MHz, Methanol-d₄) δppm 1.24 (dd, J=14.31, 6.72 Hz, 6H) 1.63 (d, J=6.85 Hz, 3H) 3.35 (m, 1H)5.31 (q, J=6.60 Hz, 1H) 7.64 (m, 1H) 7.81 (m, 2H) 7.99 (d, J=9.05 Hz,1H).

120G

Example 120 was prepared according to the general coupling-deprotectionusing Intermediate 2 and 120F. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 0.92(dd, J=13.21, 6.60 Hz, 3H) 1.31 (m, 15H) 3.93 (m, 3H) 4.46 (m, 1H) 5.04(d, J=2.20 Hz, 1H) 5.55 (m, 1H) 6.65 (m, 2H) 7.00 (m, 5H) 7.27 (m, 2H)7.65 (m, 2H) 7.99 (dd, J=22.62, 9.17 Hz, 1H) 8.94 (dd, J=54.29, 6.60 Hz,1H); LC MS 605 (M+H).

Example 121N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-vinylphenyl)acetamidetrifluoroacetic acid salt

121A Methyl 2-(3-bromophenyl)acetate

A mixture of 3-bromophenylacetic acid (5.29 g, 24.6 mmol) andconcentrated sulfuric acid (100 μL) in anhydrous methanol (40 mL) wasrefluxed overnight and then concentrated in vacuo. The residue waspartitioned between ethyl acetate and saturated sodium bicarbonatesolution. The organic layer was washed with saturated sodium bicarbonatesolution, saturated sodium chloride solution, dried (MgSO₄) andconcentrated in vacuo to give 121A (5.82 g, 100%) as pale yellow oil.LC-MS m/z: 228.18 (M+H)⁺.

121B Methyl 2-bromo-2-(3-bromophenyl)acetate

A mixture of 121A (2.28 g, 10.0 mmol) and N-bromosuccinimide (1.96 g,11.0 mmol) in carbon tetrachloride (20 mL) was deoxygenated with a flowof nitrogen for 5 min. 2,2′-Azobisisobutyronitrile (82 mg, 0.5 mmol) wasadded and the mixture was refluxed for 18 h. Hexanes was added to thecooled mixture, and the resulting solid was filtered and washed withhexanes. The filtrate was concentrated on a rotary evaporator and thenchromatographed (silica gel, step gradient from 100% hexanes to 5% ethylacetate in hexanes) to give 121B (1.3 g, 42%) as clear oil. LC-MS m/z:309.1 (M+H)⁺.

121C Methyl2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-bromophenyl)acetate

A mixture of 121B (404 mg, 1.31 mmol), Intermediate 1 (238 mg, 0.66mmol), and 2,6-lutidine (0.60 mL, 5.17 mmol) in dimethylformamide (3mL), was heated in a pressure tube at 55° C. for 3 days. The mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate and saturated sodium bicarbonate solution. The organic layer waswashed with water, saturated sodium chloride solution, dried (MgSO₄),and concentrated. Chromatography (silica gel, 30% ethyl acetate inhexanes) gave 121C (263 mg, 68%) as yellow oil which solidified uponstanding. LC-MS m/z: 586.2 (M+H)⁺.

121D2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-bromophenyl)aceticacid

A mixture of 121C (600 mg, 1.03 mmol) and lithium hydroxide monohydrate(86 mg, 2.05 mmol) in THF (4 mL), water (4 mL), and methanol (1 mL) wasstirred at rt for 1 h. The mixture was concentrated in vacuo, and theresidue was partitioned between ethyl acetate and 1N hydrochloric acidsolution. The organic layer was washed with saturated ammonium chloridesolution, water, saturated sodium chloride solution, dried (MgSO₄), andconcentrated to give 121D (547 mg, 93%) as yellow solid. LC-MS m/z:572.1 (M+H)⁺.

121EN-(2-(methylsulfonyl)benzyl)-2-(3-bromophenyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)acetamide

To a mixture of 121D (547 mg, 0.96 mmol) and Intermediate 6 (340 mg,1.54 mmol) in dimethylformamide (3 mL) and dichloromethane (20 mL),diisopropylethylamine (0.55 mL, 3.15 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (392 mg,2.04 mmol) and 1-hydroxy-7-azabenzotriazole (278 mg, 2.04 mmol) wereadded. The reaction mixture was stirred at rt overnight. The solvent wasevaporated and ice water was added. The resulting solid was filtered andwashed with water. The solid was purified by silica gel chromatography(100% chloroform, followed by 10% methanol in chloroform). The productfractions were combined and triturated with hexanes, filtered, andwashed with hexanes to afford 121E (614 mg, 81%) as yellow solid. LC-MSm/z: 739.1 (M+H)⁺.

121FN-(2-(Methylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-vinylphenyl)acetamide

A suspension of 121E (150 mg, 0.2 mmol), potassium carbonate (40 mg,0.28 mmol) and 2,4,6-trivinylcyclotriboroxane pyridine complex (80 mg,0.22 mmol in ethyleneglycol dimethyl ether (2 mL) and water (0.5 mL) inpressure tube was deoxygenated with a nitrogen flow for 3 min.

Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) was added.The mixture was heated at 90° C. for 1 h. The reaction mixture waschromatographed (silica gel, 10% methanol in chloroform) to give 121F(124 mg, 89%). LC-MS m/z: 687.3 (M+H)⁺.

21G

Example 121: A solution of 121F (35 mg, 0.05 mmol) in ethyl acetate (1.5mL) and 4N hydrogen chloride in dioxane (1.5 mL) was stirred overnightat rt. The solvent was evaporated and the crude material was purified byreversed-phase HPLC to afford Example 121 (15 mg, 49%) as a whiteamorphous solid. LC-MS m/z: 487.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.81(t, 0.5H), 8.07 (d, 1H), 7.90 (m, 1H), 7.61 (m, 1H), 7.45-7.44 (m, 7H),7.19 (dd, 1H), 6.80 (dd, 1H), 6.63 (dd, 1H), 6.66 (d, 1H), 5.81 (d, 1H),5.28 (d, 1H), 5.21 (s, 1H), 4.88-4.77 (m, 2H), 3.15 (s, 3H).

Example 122N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethylphenyl)acetamidetrifluoroacetic acid salt

122AN-(2-(Methylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-ethylphenyl)acetamide

To a solution of 121F (50 mg, 0.07 mmol) in methanol (2 mL), 10%palladium on carbon (23 mg) was added. The reaction flask was evacuated,flushed with nitrogen (3×), and then stirred under hydrogen (65 psi) for2 h. The reaction mixture was filtered and concentrated to afford crude122A which was used as is in the next step. LC-MS m/z: 689.2 (M+H)⁺.

122B

Example 122: A solution of 122A in ethyl acetate (1.5 mL) and 4Nhydrogen chloride in dioxane (1.5 mL) was stirred overnight at rt. Thesolvent was evaporated and the crude material was purified byreversed-phase HPLC to afford Example 122 (17 mg, 39%, 2 steps) as awhite amorphous solid. LC-MS m/z: 489.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.87 (t, 0.75H), 8.07 (d, 1H), 7.45 (m, 2H), 7.37-7.29 (m, 5H),7.23-7.16 (m, 2H), 6.78 (d, 1H), 6.65 (d, 1H), 5.17 (s, 1H), 4.87-4.67(m, 2H), 3.14 (s, 3H), 2.64 (q, 2H), 1.21 (t, 3H).

Example 123N-(3-(Benzenesulfonamide)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethylphenyl)acetamidetrifluoroacetic acid salt

123AN-(3-(Menzenesulfonamide)-2-(3-bromophenyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)acetamide

To a mixture of 121D (299 mg, 0.51 mmol) and Intermediate 5 (170 mg,0.76 mmol) in dimethylformamide (2 mL) and dichloromethane (10 mL),diisopropylethylamine (0.267 mL, 1.53 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (196 mg,1.02 mmol) and 1-hydroxy-7-azabenzotriazole (139 mg, 1.02 mmol) wereadded. The reaction mixture was stirred at 4 h. The solvent wasevaporated and ice water was added. The resulting solid was filtered andwashed with water. The solid was purified by silica gel chromatography(100% chloroform, followed by 10% methanol in chloroform). The productfractions were combined to afford 123A (0.33 g, 88%) as a yellow foam.LC-MS m/z: 740.1 (M+H)⁺.

123BN-(3-(Benzenesulfonamide)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-vinylphenyl)acetamide

A suspension of 123A (74 mg, 0.1 mmol), potassium carbonate (20 mg, 0.14mmol) and 2,4,6-trivinylcyclotriboroxane pyridine complex (40 mg, 0.11mmol in ethyleneglycol dimethyl ether (2 mL) and water (0.5 mL) inpressure tube was deoxygenated under a flow of nitrogen for 3 min.Tetrakis(triphenylphosphine)palladium(0) (5.5 mg, 0.005 mmol) was added.The mixture was heated at 90° C. for 1 h. The reaction mixture waschromatographed (silica gel, 10% methanol in chloroform) to give 123B(40 mg, 60%). LC-MS m/z: 688.2 (M+H)⁺.

123CN-(3-(Benzenesulfonamide)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-ethylphenyl)acetamide

To a solution of 123B (40 mg, 0.06 mmol) in methanol (4 mL), 10%palladium on carbon (23 mg) was added. The reaction flask was evacuated,flushed with nitrogen (3×), and then stirred under hydrogen (60 psi) for1 h. The reaction mixture was filtered, concentrated to afford crude123C which was used as is in the next step. LC-MS m/z: 690.3 (M+H)⁺.

123D

Example 123: A solution of 123C in ethyl acetate (1.5 mL), 4N hydrogenchloride in dioxane (1.5 mL) was stirred overnight at rt. The solventwas evaporated and the crude material was purified by reversed-phaseHPLC to afford Example 123 (16 mg, 46%, 2 steps) as a white amorphoussolid. LC-MS m/z: 490.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.98 (t,0.75H), 8.07 (d, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.38-7.30 (m, 6H),7.22-7.16 (m, 2H), 6.80 (d, 1H), 6.5 (d, 1H), 5.14 (s, 1H), 4.47 (d,2H), 2.65 (q, 2H), 1.27 (t, 3H).

Example 124N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-methoxyphenyl)acetamidetrifluoroacetic acid salt

124A2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-methoxyphenyl)aceticacid

A mixture of 3-methoxyphenylboronic acid (76 mg, 0.5 mmol), Intermediate1 (90 mg, 0.25 mmol), and glyoxylic acid (0.23 mg, 0.25 mmol) in DCE(1.3 mL), was heated in a pressure tube at 60° C. for 5 h. The mixturewas chromatographed (silica gel, 10% methanol in chloroform) to give124A (72 mg, 56%). LC-MS m/z: 524.3 (M+H)⁺.

124BN-(2-(Methylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-methoxyphenyl)acetamide

To a mixture of 124A (36 mg, 0.07 mmol) and Intermediate 6 (27 mg, 0.12mmol) in dimethylformamide (0.2 mL) and dichloromethane (1 mL),diisopropylethylamine (0.05 mL, 0.28 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.18mmol) and 1-hydroxy-7-azabenzotriazole (24 mg, 0.18 mmol) were added.The reaction mixture was stirred at RT for 6 h. The solvent wasconcentrated in vacuo. The residue was purified by silica gelchromatography (10% to 100% ethyl acetate in hexanes to give 124B. LC-MSm/z: 691.3 (M+H)⁺.

124C

Example 124: A solution of 124B in ethyl acetate (1 mL) and 4N hydrogenchloride in dioxane (1 mL) was stirred overnight at RT. The solvent wasevaporated and the crude material was purified by reversed-phase HPLC toafford Example 124 (30 mg, 71%, 2 steps) as a pale yellow amorphoussolid. LC-MS m/z: 491.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.78 (t,0.75H), 8.06 (d, 1H), 7.91 (dd, 1H), 7.45 (m, 2H), 7.31 (m, 3H), 7.22(dd, 1H), 7.11 (m, 2H), 6.92 (dd, 1H), 6.76 (d, 1H), 6.5 (d, 1H), 5.19(s, 1H), 4.89-4.68 (m, 2H), 3.77 (s, 3H), 3.15 (s, 3H).

Example 125N-(3-(Benzenesulfonamide)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-methoxyphenyl)acetamidetrifluoroacetic acid salt

125AN-(3-(Benzenesulfonamide)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-methoxyphenyl)acetamide

To a mixture of 124A (36 mg, 0.07 mmol) and Intermediate 5 (27 mg, 0.12mmol) in dimethylformamide (0.2 mL) and dichloromethane (1 mL),diisopropylethylamine (0.04 mL, 0.23 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.18mmol) and 1-hydroxy-7-azabenzotriazole (22 mg, 0.16 mmol) were added.The reaction mixture was stirred at rt for 6 h. The solvent wasconcentrated in vacuo. The residue was purified by silica gelchromatography (10% to 100% ethyl acetate in hexanes to give 125A. LC-MSm/z: 692.3 (M+H)⁺.

125B

Example 125: A solution of 125A in ethyl acetate (1 mL) and 4N hydrogenchloride in dioxane (1 mL) was stirred overnight at rt. The solvent wasevaporated and the crude material was purified by reversed-phase HPLC toafford Example 125 (17 mg, 40%, 2steps) as a pale yellow amorphoussolid. LC-MS m/z: 492.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.0 (t, 0.5H),8.07 (dd, 1H), 7.78 (dd, 1H), 7.74 (m, 1H), 7.39-7.29 (m, 4H), 7.19-7.11(m, 3H), 6.91 (dd, 1H), 6.80 (dd, 1H), 6.65 (d, 1H), 5.15 (s, 1H), 4.46(d, 2H), 3.77 (s, 3H).

Example 126N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-methylthiophenyl)acetamidetrifluoroacetic acid salt

126A2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-methylthiophenyl)aceticacid

A mixture of 3-methylthiophenylboronic acid (84 mg, 0.5 mmol),Intermediate 1 (90 mg, 0.25 mmol), and glyoxylic acid (0.23 mg, 0.25mmol) in DCE (1.25 mL), was heated in a pressure tube at 60° C. for 6 h.The mixture was chromatographed (silica gel, 10% methanol in chloroform)to give 126A (86 mg, 69%). LC-MS m/z: 540.3 (M+H)⁺.

126BN-(2-(Methylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-methylthiophenyl)acetamide

To a mixture of 126A (43 mg, 0.08 mmol) and Intermediate 6 (27 mg, 0.12mmol) in dimethylformamide (0.2 mL) and dichloromethane (1 mL),diisopropylethylamine (0.03 mL, 0.17 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.16mmol) and 1-hydroxy-7-azabenzotriazole (22 mg, 0.16 mmol) were added.The reaction mixture was stirred at RT overnight. The solvent wasconcentrated in vacuo. Water was added to the residue and the solid wasfiltered. The solid was purified by silica gel chromatography (30% to100% ethyl acetate in hexanes) to give 126B (28 mg, 50%). LC-MS m/z:707.2 (M+H)⁺.

126C

Example 126: A solution of 126B in ethyl acetate (1 mL) and 4N hydrogenchloride in dioxane (1 mL) was stirred overnight at rt. The solvent wasevaporated and the crude material was purified by reversed-phase HPLC toafford Example 126 (22 mg, 89%) as an off white amorphous solid. LC-MSm/z: 491.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.80 (t, 0.5H), 8.07 (d,1H), 7.91 (dd, 1H), 7.51-7.42 (m, 3H), 7.42-7.31 (m, 4H), 7.29-7.24 (m,1H), 7.19 (dd, 1H), 6.89 (d, 1H), 6.66 (d, 1H), 5.19 (s, 1H), 4.90-4.69(m, 2H), 3.15 (s, 3H), 2.45 (s, 3H).

Example 127N-(3-(Benzenesulfonamide)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-methylthiophenyl)acetamidetrifluoroacetic acid salt

127AN-(3-(Benzenesulfonamide)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-methylthiophenyl)acetamide

To a mixture of 126A (43 mg, 0.08 mmol) and Intermediate 5 (27 mg, 0.12mmol) in dimethylformamide (0.2 mL) and dichloromethane (1 mL),diisopropylethylamine (0.03 mL, 0.17 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.16mmol) and 1-hydroxy-7-azabenzotriazole (22 mg, 0.16 mmol), were added.The reaction mixture was stirred at rt overnight. The solvent wasconcentrated in vacuo. Water was added to the residue and the solid wasfiltered. The solid was purified by silica gel chromatography (30% to100% ethyl acetate in hexanes) to give 127A (28 mg, 50%). LC-MS m/z:708.2 (M+H)⁺.

127B

Example 127: A solution of 127A in ethyl acetate (1 mL) and 4N hydrogenchloride in dioxane (1 mL) was stirred overnight at RT. The solvent wasevaporated and the crude material was purified by reversed-phase HPLC toafford Example 127 (19 mg, 76%) as a pale yellow amorphous solid. LC-MSm/z: 508.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.0 (t, 0.5H), 8.07 (d,1H), 7.79 (bs, 1H), 7.75 (m, 1H), 7.44 (bs, 1H), 7.39-7.30 (m, 6H), 7.26(m, 1H), 7.19 (dd, 1H), 6.80 (d, 1H), 6.64 (dd, 1H), 5.15 (s, 1H), 4.47(d, 2H), 2.46 (s, 3H).

Example 128N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-allylphenyl)acetamidetrifluoroacetic acid salt

128AN-(2-(Methylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-allylphenyl)acetamide

A suspension of 121E (569 mg, 0.5 mmol), and allyl tributyltin (0.155mL, 0.22 mmol) in toluene (3 mL) in a pressure tube was deoxygenatedunder a flow of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (29mg, 0.025 mmol) was added. The mixture was heated at 100° C. overnight.The reaction mixture was chromatographed (silica gel, gradient 30% to100% ethyl acetate in hexanes) to give 128A (225 mg, 64%). LC-MS m/z:701.3 (M+H)⁺.

128B

Example 128: A solution of 128A (36 mg, 0.05 mmol) in ethyl acetate (1.5mL) and 4N hydrogen chloride in dioxane (1.5 mL) was stirred overnightat rt. The solvent was evaporated and the crude material was purified byreversed-phase HPLC to afford Example 128 (10 mg, 32%) as a whiteamorphous solid. LC-MS m/z: 501.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.81(t, 1H), 8.07 (d, 1H), 7.90 (m, 1H), 7.49-7.44 (m, 2H), 7.38-7.33 (m,5H), 7.19-7.17 (m, 2H), 6.80 (d, 1H), 6.65 (d, 1H), 5.93 (m, 1H), 5.17(s, 1H), 5.04 (m, 2H), 4.88-4.68 (m, 2H), 3.31-3.34 (2d, 2H), 3.15(s.3H).

Example 129N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-propylphenyl)acetamidetrifluoroacetic acid salt

129AN-(2-(Methylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-propylphenyl)acetamide

To a solution of 128A (40 mg, 0.057 mmol) in methanol (5 mL), 10%palladium on carbon (24 mg) was added. The reaction flask was evacuated,flushed with nitrogen (3×), and then stirred under hydrogen (60 psi) for1.2 h. The reaction mixture was filtered and concentrated to affordcrude 129A which was used as is in the next step. LC-MS m/z: 703.3(M+H)⁺.

129B

Example 129: A solution of 129A in ethyl acetate (1.5 mL) and 4Nhydrogen chloride in dioxane (1.5 mL) was stirred overnight at rt. Thesolvent was evaporated and the crude material was purified byreversed-phase HPLC to afford Example 129 (10 mg, 28%, 2 steps) as awhite amorphous solid. LC-MS m/z: 503.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.75 (t, 1H), 8.07 (d, 1H), 7.91 (m, 1H), 7.48-7.42 (m, 2H), 7.36-7.29(m, 5H), 7.20-7.17 (m, 2H), 6.79 (d, 1H), 6.65 (d, 1H), 5.16 (s, 1H),4.88-4.67 (m, 2H), 3.14 (s, 3H), 2.59 (t, 2H), 1.60 (m, 2H), 0.91 (t,3H).

Example 130N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-(p)prop-1-en-2-yl)phenyl)acetamidetrifluoroacetic acid salt

130AN-(2-(Methylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-(prop-1-en-2-yl)phenyl)acetamide

Isopropenyl magnesium bromide (5 mL 0.5M solution, 2.5 mmol) was addeddropwise to a stirring solution of trimethyl borate (0.84 mL, 7.5 mmol)in THF (3 mL). The cloudy solution was stirred at rt for 2 h, cooled to0° C. and treated with 1N aqueous hydrochloric acid (3 mL) dropwise.After 15 min the solution was extracted with 3×25 mL diethyl ether. Theorganic layer was washed with saturated sodium chloride solution, dried(MgSO₄) and concentrated in vacuo to give prop-1-en-2-ylboronic acid asa white solid (340 mg, >100%). A suspension of 121E(165 mg, 0.22 mmol),prop-1-en-2-ylboronic acid (60 mg, 0.7 mmol) and potassium carbonate(156 mg, 1.13 mmol) in a mixture of ethyleneglycol dimethylether (2 mL)and water (0.22 mL) in a pressure tube was deoxygenated under a flow ofnitrogen. Dichloro[1,1′-bis(diphenylphosphino) ferrocene] palladium(II)dichloromethane adduct (18 mg, 0.025 mmol) was added. The mixture washeated at 90° C. for 1.2 h. The reaction mixture was chromatographed(silica gel, gradient from 30% to 100% ethyl acetate in hexanes) to give130A (125 mg, 80%). LC-MS m/z: 701.4 (M+H)⁺.

130B

Example 130: A solution of 130A (40 mg, 0.057 mmol) in ethyl acetate (1mL) and 4N hydrogen chloride in dioxane (1 mL) was stirred overnight atrt. The solvent was evaporated and the crude material was purified byreversed-phase HPLC to afford Example 130 (5 mg, 14%) as a beigeamorphous solid. LC-MS m/z: 501.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.80(t, 0.75H), 8.08 (d, 1H), 7.91 (m, 1H), 7.46 (m, 1H), 7.51-7.31 (m, 7H),7.19 (m, 1H), 6.81 (d, 1H), 6.67 (m, 1H), 5.38 (s, 1H), 5.21-5.11 (m,2H), 4.88-4.73 (m, 2H), 3.15 (s, 3H), 2.13 (s.3H).

Example 131N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-isopropylphenyl)acetamidetrifluoroacetic acid salt

131AN-(2-(Methylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-isopropylphenyl)acetamide

To a solution of 130A (40 mg, 0.057 mmol) in methanol (5 mL), 10%palladium on carbon (28 mg) was added. The reaction flask was evacuated,flushed with nitrogen (3×), and then stirred under hydrogen (60 psi) for2 h. The reaction mixture was filtered, concentrated to afford crude131A which was used as is in the next step. LC-MS m/z: 703.4 (M+H)⁺.

131B

Example 131: A solution of 131A in ethyl acetate (1 mL) and 4N hydrogenchloride in dioxane (1 mL) was stirred overnight at rt. The solvent wasevaporated and the crude material was purified by reversed-phase HPLC toafford Example 131 (24 mg, 69%, 2 steps) as a pale pink amorphous solid.LC-MS m/z: 503.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) 8.07 (d, 1H), 7.91 (m,1H), 7.47-7.44 (m, 2H), 7.39 (bs, 1H), 7.34-7.29 (m, 4H), 7.26 (m, 1H),7.19 (dd, 1H), 6.80 (d, 1H), 6.65 (d, 1H), 5.16 (s, 1H), 4.90-4.69 (m,2H), 3.14 (s, 3H), 2.90 (m, 1H), 1.22 (d, 6H).

Example 132N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-cyclopropylphenyl)acetamidetrifluoroacetic acid salt and Example 133N-(2-(Methylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-bromophenyl)acetamidetrifluoroacetic acid salt

132AN-(2-(Methylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)isoquinolin-6-ylamino)-2-(3-cyclopropylphenyl)acetamide

A suspension of 121E (111 mg, 0.15 mmol), cyclopropylboronic acid (40mg, 0.71 mmol), and potassium carbonate (104 mg, 0.75 mmol) in a mixtureof ethyleneglycol dimethylether (1.3 mL) and water (0.15 mL) in apressure tube was deoxygenated under a flow of nitrogen.Dichloro[1,1′-bis(diphenylphosphino) ferrocene] palladium(II)dichloromethane adduct (12 mg, 0.016 mmol) was added. The mixture washeated at 90° C. for 3 h. The reaction mixture was chromatographed(silica gel, gradient from 10% to 100% ethyl acetate in hexanes) to givea 1:2 mixture of 132A and 121E (30 mg). LC-MS m/z: 701.3, 741.1 (M+H)⁺.

132B

Example 132 and Example 133: To a mixture of 132A and 121E (40 mg, 0.057mmol) in ethyl acetate (1 mL) was added 4 N hydrogen chloride in dioxane(1 mL). The mixture was stirred overnight at rt. The solvent wasevaporated and the crude material was purified by reversed-phase HPLC toafford Example 132 (6 mg, 7%) and Example 133 (14 mg, 14%) as whiteamorphous solids. Example 132: LC-MS m/z: 501.4 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.74 (t, 0.75H), 8.07 (d, 1H), 7.92 (dd, 1H), 7.49-7.45 (m,2H), 7.34-7.24 (m, 5H), 7.19 (dd, 1H), 7.08 (m, 1H), 6.80 (d, 1H), 6.65(d, 1H), 5.14 (s, 1H), 4.88-4.68 (m, 2H), 3.15 (s, 3H), 1.91 (m, 1H),0.96 (m, 2H), 0.67 (m, 2H). Example 133: LC-MS m/z: 539.2 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.84 (t, 0.1H), 8.08 (d, 1H), 7.92 (dd, 1H), 7.72 (m,1H), 7.54-7.44 (m, 4H), 7.35-7.31 (m, 3H), 7.17 (dd, 1H), 6.80 (d, 1H),6.66 (d, 1H), 5.23 (s, 1H), 4.89-4.70 (m, 2H), 3.17 (s, 3H)

Example 134N-(3-(Cyclopropylsulfonyl)benzyl)-2-(1-aminophthalazin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

134A 4-Bromo-N-diethylbenzamide

Oxalyl chloride (3.5 mL, 40.1 mmol) was added dropwise to a solution of

4-bromobenzoic acid (4.08 g, 20.3 mmol) and dimethyl formamide (0.04 mL)in anhydrous DCE (50 mL) at 0° C. The mixture was stirred for 2 h at rt,concentrated in vacuo and coevaporated with toluene twice. The residuewas dissolved in anhydrous DCE (25 mL) and cooled in an ice bath.Diethyl amine (5 mL, 48.3 mmol) in DCE (25 mL) was added dropwise. Thereaction was stirred overnight and then concentrated in vacuo. Theresidue was treated with 1N hydrochloric acid solution and extractedtwice with dichloromethane. The organic layer was washed with water andsaturated sodium chloride solution, dried (MgSO₄), and concentrated invacuo to give 134A (4.87 g, 94%) as a pink solid. LC-MS m/z: 588.19(M+H)⁺.

134B 4-Bromo-N,N-diethyl-2-formylbenzamide

An oven dried round bottom flask was charged with anhydrous THF (20 mL)and 2,2,6,6-tetramethyl piperidine (0.68 mL, 4.0 mmol). The mixture wascooled in an ice bath and 1.46 M n-butyl lithium in hexane (2.8 mL, 4.09mmol) was added dropwise over 5 min. After 10 min, the solution wascooled to −78° C. and a solution of 134A (512 mg, 2.0 mmol) in anhydrousTHF (2 mL) was added quickly down the side of flask to precool thesolution. After 1 h at −78° C. dimethyl formamide (0.5 mL, 6.38 mmol)was added dropwise and the mixture was stirred at −78° C. for 20 min andat RT for 30 min. Water was added dropwise followed by ethyl acetate.The mixture was extracted twice with ethyl acetate. The organic layerwas washed with water, saturated sodium chloride solution, dried (MgSO₄)and concentrated in vacuo to give 134B (0.256 g, 45%) as yellow oil.LC-MS m/z: 286.16 (M+H)⁺.

134C 5-Bromo-3-hydroxyisobenzofuran-1(3H)-one

A solution of 134B (1.15 g, 4.05 mmol) in 6N hydrochloric acid (20 mL),was heated at 105° C. overnight. After cooling, the reaction mixture wasextracted with ethyl acetate (4×50 mL). The combined organic layers werewashed with water, saturated sodium chloride solution, dried (MgSO₄),and concentrated to give 134C (904 mg, 97%) as a beige solid. LC-MS m/z:228.91 (M−H).

134D 6-Bromophthalazin-1(2H)-one

134C (954 mg, 4.17 mmol) was suspended in isopropyl alcohol (10 mL). Thesolution was heated at 90° C. for 1.5 h. Hydrazine monohydrate (0.4 mL,8.25 mmol) was added in 4 increments. The resulting suspension wasfiltered and washed with isopropyl alcohol to give 134D (813 mg, 87%) asa beige solid. LC-MS m/z: 227.12 (M+H)⁺.

134E 6-Bromo-1-chlorophthalazine

A suspension of 134D (315 mg, 1.4 mmol) and phosphorus oxychloride (2mL) was heated at 110° C. for 1 h. The reaction mixture was cooled to rtand the solvent was evaporated in vacuo. The residue was cooled in anice bath and cold water and 1N NaOH solution were added until themixture was basic. The yellow solid was filtered and washed with waterto afford 134E (295 mg, 87%). LC-MS m/z: 245.13 (M+H)⁺.

134F 6-Bromophthalazin-1-amine

A solution of 134E (200 mg, 0.83 mmol) in saturated ammonia solution inethylene glycol (3 mL) was heated to 130° C. overnight in a pressuretube. The reaction mixture was concentrated and the residue waschromatographed (silica gel, chloroform, 5% methanol in chloroform) togive 134F (164 mg, 89%). LC-MS m/z: 226.2 (M+H)⁺.

134G 6-Bromo-1-(N,N-di-tert-butoxycarbonylamino)phthalazine—

A solution of 134F (130 mg, 0.58 mmol), 4-dimethylaminopyridine (4 mg,0.03 mmol) and di-tert-butyl dicarbonate (382 mg, 1.75 mmol) inacetonitrile (5 mL) was stirred overnight at rt. The solvent wasevaporated and the crude material was purified by silica gelchromatography (0-50% ethyl acetate in hexane) to afford 134G (100 mg,41%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 9.45 (s, 1H), 8.21 (d,1H), 8.04 (dd, 1H), 7.85 (d, 1H), 1.32 (s, 18H).

134H Methyl2-(1-(di-tert-butoxycarbonylamino)phthalazin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetate

A suspension of 134G (100 mg, 0.24 mmol), Intermediate 13B (63 mg, 0.24mmol), cesium carbonate (285 mg, 0.87 mmol) andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (8 mg, 0.013 mmol) andtoluene (3 mL) in pressure tube was deoxygenated under a flow ofnitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium(0) (5 mg,0.005 mmol) was added. The mixture was heated at 100° C. overnight. Thereaction mixture was purified by preparative LC-MS to afford to afford134H (39 mg, 27%). LC-MS m/z: 611.3 (M+H)⁺.

134I2-(1-(di-tert-butoxycarbonylamino)phthalazin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid

A mixture of 134H (39 mg, 0.063 mmol) and lithium hydroxide monohydrate(5.4 mg, 0.13 mmol) in THF (1 mL) and water (1 mL) was stirred at rt for2 h. Additional lithium hydroxide monohydrate (2.7 mg, 0.06 mmol) wasadded and the mixture was stirred for 1 h. The mixture was concentratedin vacuo, and the residue was partitioned between ethyl acetate and 1Nhydrochloric acid solution. The organic layer was dried (MgSO₄), andconcentrated to give 134I (40 mg, 100%) as a yellow glass. LC-MS m/z:597.3 (M+H)⁺.

134JN-(3-(Cyclopropylsulfonyl)benzyl)-2-(1-(di-tert-butoxycarbonylamino)phthalazin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamide

To a solution of 134I (30 mg, 0.05 mmol) in dimethylformamide (0.5 mL)was added diisopropylethylamine (0.025 mL, 0.15 mmol), Intermediate 7(24 mg, 0.069 mmol), andbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(33 mg, 0.075 mmol). The reaction mixture was stirred at rt for 0.5 h.The solvent was evaporated and the residue was purified byreversed-phase HPLC to afford 134J. LC-MS m/z: 790.3 (M+H)⁺.

134K

Example 134: A solution of 134J in ethyl acetate (1 mL) and 4N hydrogenchloride in dioxane (1 mL) was stirred overnight at rt. The solvent wasevaporated and the crude material was purified by reversed-phase HPLC toafford Example 134 (2.5 mg, 7%, 2steps) as a white amorphous solid.LC-MS m/z: 590.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD δ): 8.59 (t, 1H), 8.38(s, 1H), 8.16 (d, 1H), 7.81 (d, 1H), 7.49 (m, 2H), 7.39 (m, 2H), 7.08(s, 1H), 7.05 (d, 1H), 6.97 (d, 1H), 6.85 (s, 1H), 5.15 (s, 1H),4.88-4.74 (m, 2H), 4.54 (m, 1H), 3.99 (m, 2H), 2.80 (m, 1H), 1.37 (t,3H), 1.30 (d, 6H), 1.21 (m, 1H), 1.13 (m, 1H), 1.00 (m, 2H).

Example 135N-(2-(Cyclopropylsulfonyl)benzyl)-2-(3-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

135A 2-(Bromomethyl)-4-nitrobenzonitrile

A suspension of 2-methyl-4-nitrobenzonitrile (0.872 g, 5.28 mmol) andN-bromosuccinimide (1.16 g, 6.52 mmol, recrystallized from water) incarbon tetrachloride (25 mL) was irradiated with a sun lamp for 16 h.The reaction mixture was concentrated under reduced pressure and theresidue was purified by chromatography on silica gel (gradient from 0 to15% ethyl acetate in hexanes) to afford 135A (0.610 g, 48%). ¹H NMR (400MHz, CDCl₃, δ): 8.44 (d, J=2.2 Hz, 1H), 8.29 (dxd, J=8.3 Hz, 1H), 7.90(d, J=8.3 Hz, 1H), 4.70 (s, 2H).

135B 2-(Cyanomethyl)-4-nitrobenzonitrile

To a solution of sodium cyanide (99.5 mg, 2.03 mmol) in water (0.5 mL)at 0° C. was added carefully sulfuric acid (0.95 mL, diluted 10% w/wwith water). Caution: this reaction generates hydrogen cyanide and mustbe performed in a fume hood with good ventilation. A solution of 135A(48 mg, 0.2 mmol) in acetonitrile (2 mL) was added all at once. Thereaction was heated to 80° C. for 4 h, adding additional crystals ofsodium cyanide several times to raise the pH to ˜9. The reaction mixturewas extracted three times with methylene chloride and the combinedorganics were washed with water and brine, dried (MgSO₄), andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (gradient of 0 to 30% ethyl acetate in hexanes) togive 135B (20 mg, 53%). ¹H NMR (400 MHz, CDCl₃, δ): 8.55 (d, J=1.8 Hz,1H), 8.37 (dxd, J=8.4, 2.2 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 4.14 (s,2H).

135C N-(1-Bromo-6-nitroisoquinolin-3-yl)acetamide

Hydrogen bromide in acetic acid (1.5 mL, 33% solution) was added to 135B(54 mg, 0.29 mmol). After six hours, the reaction mixture wasconcentrated under reduced pressure. The residual orange solid wastriturated with a sodium acetate solution (144 mg in 11 mL water),filtered, washed with water, and coevaporated with methanol anddichloromethane to give 135C (71 mg, 89%) as a yellow solid. LC-MS m/z:310.2 (M+H)⁺.

135D N-(6-Aminoisoquinolin-3-yl)acetamide

A suspension of 135C (70 mg, 0.23 mmol) and 10% palladium/carbon (20 mg)in ethanol (6 mL) was hydrogenated (50 psi) for 3 h. Methanol andhydrogen chloride (0.5 mL, 4 N solution in dioxanes) were added todissolve the product. The solution was filtered and concentrated underreduced pressure to give 135D (57 mg, 100%) as a yellow solid. LC-MSm/z: 202.3 (M+H)⁺.

135E Methyl2-(3-acetamidoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetate

A solution of 135D (53 mg, 0.23 mmol) and methyl2-chloro-2-(3-ethoxy-4-isopropoxyphenyl)acetate (66 mg, 0.23 mmol, seeWO 2004/072101 for synthesis), and N,N-diisopropylethylamine (0.1 mL) indimethylformamide (2 mL) was heated at 90° C. for 5 h. The reactionmixture was concentrated and the residue was purified by chromatographyon silica gel (gradient from 0 to 100% ethyl acetate in hexanes) to give135E (22 mg, 21%) as a red glass. LC-MS m/z: 452.3 (M+H)⁺.

135F2-(3-acetamidoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid

Lithium hydroxide solution (0.1 mL of 500 mg LiOH in 10 mL water) wasadded to a solution of 135E (22 mg, 0.049 mmol) in tetrahydrofuran (1mL) and water (1 mL). After 1.5 h, an additional aliquot of lithiumhydroxide solution (0.1 mL) was added. After an additional 1 h, thereaction was concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and hydrochloric acid (1 N). Theorganic layer was dried (MgSO₄) and concentrated under reduced pressureto give 135F (21 mg, 100%) as a yellow film. LC-MS m/z: 438.3 (M+H)⁺.

135G

Example 135: A solution of 1-35F (21 mg, 0.048 mmol), Intermediate 7 (24mg, 0.098 mmol), and DIEA (0.025 mL, 0.14 mmol) in DMF (0.5 mL) wastreated with BOP (32 mg, 0.072 mmol). The reaction mixture was stirredovernight at rt and then concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC to afford 4 mg of acetylatedproduct. This material was dissolved in methanol (several mL) andtreated with sodium hydroxide (0.020 g) and lithium hydroxide solution(0.1 mL of 0.5 g lithium hydroxide in 10 mL water). The reaction mixturewas refluxed overnight and then concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC to afford Example 135 (1.4mg, 5%) as a yellow amorphous solid. LC-MS m/z: 589.3 (M+H)⁺.

Example 136N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-amino-8-fluoroisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

136A (E)-methyl 3-(3-amino-5-fluorophenyl)acrylate

A mixture of 1-fluoro-3-iodo-5-nitrobenzene (1.145 g, 4.29 mmol), sodiumacetate (0.430 g, 5.24 mmol), palladium(II) acetate (1.7 mg, 0.0076mmol), methyl acrylate (0.425 mL, 4.71 mmol), and1-methyl-2-pyrrolidinone (11 mL) under argon was degassed with threefreeze/pump/thaw cycles. The reaction mixture was heated to 130° C. for35 min and then at 100° C. for 14 h. The reaction mixture was dilutedwith water and saturated sodium bicarbonate solution and extracted threetimes with diethyl ether. The combined organic extracts were washed withsaturated sodium bicarbonate solution, hydrochloric acid (1N), andbrine, dried (MgSO₄), and concentrated under reduced pressure. Theresidue was suspended in a mixture of ethanol (12 mL), water (2.5 mL),and acetic acid (1.25 mmol) and heated to reflux. Iron powder (0.519 g,9.28 mmol) was added portionwise over 30 min, and reflux was continuedfor an additional 30 min. The reaction mixture was concentrated underreduced pressure. The residue was partitioned between ethyl acetate andsodium bicarbonate solution and filtered through a glass fibre filter toremove a fine grey precipitate. The aqueous phase was extracted withethyl acetate (3×) and the organic phase was dried (MgSO₄) andconcentrated under reduced pressure to give 136A (0.328 g, 74%) as apale yellow solid. LC-MS m/z: 196.2 (M+H)⁺.

136B (E)-Methyl 3-(3-(dibenzylamino)-5-fluorophenyl)acrylate

Benzyl bromide (0.440 mL, 3.70 mmol) was added to a solution of 136A(0.328 g, 1.68 mmol) and DIEA (0.880 mL) in acetonitrile (5 mL). Thereaction mixture was heated at 60° C. for 14 h and then concentratedunder reduced pressure. The residual solid was triturated twice withdiethyl ether, dissolved in dichloromethane, and extracted withhydrochloric acid (1N) and saturated sodium bicarbonate solution. Theorganic layer was dried (MgSO₄) and concentrated under reduced pressure.The residue was purified by silica gel chromatography (gradient from 0to 15% ethyl acetate in hexanes) to give 136B (0.468 g, 74%) as a whitesolid. LC-MS m/z: 376.5 (M+H)⁺.

136C (E)-3-(3-(Dibenzylamino)-5-fluorophenyl)acrylic acid

Sodium hydroxide (2 mL, 2 mmol, 1.00 N solution) was added to a solutionof 136B (0.467 g, 1.24 mmol) in tetrahydrofuran (2 mL) and methanol (1mL). The reaction was heated at 80° C. for 1 h. Hydrochloric acid (1 N)was added and the reaction mixture was extracted with ethyl acetate(2×). The combined organic layers were dried (MgSO₄) and concentratedunder reduced pressure to give 136C (0.411 g, 91%) as a pale yellowsolid. LC-MS m/z: 362.4 (M+H)⁺.

136D 6-(Dibenzylamino)-8-fluoroisoquinolin-1(2H)-one

A solution of ethyl chloroformate (0.421 mL, 4.4 mmol) in acetone (10mL) was added dropwise to a suspension of 136C (1.46 g, 4.0 mmol) in amixture of acetone (50 mL) and triethylamine (1.25 mL, 9.0 mmol) at 0°C. The reaction mixture was stirred for 45 min and then a solution ofsodium azide (0.478 g 7.4 mmol) in water (14 mL) was added dropwise over1 h. After an additional 1 h, the reaction was warmed to rt, poured intowater, and extracted with dichloromethane (3×). The combined organiclayers were washed with water and brine, dried (MgSO₄), and concentratedunder reduced pressure to give a yellow solid (1.5 g). (Caution: thisacyl azide intermediate is potentially explosive and should be handledin small quantities behind a safety shield.) A portion of this solid(0.488 g) was dissolved in a mixture of dichloromethane (1 mL) andphenyl ether (3 mL) and added slowly dropwise to a refluxing mixture ofphenyl ether (3 mL) and tributylamine (0.8 mL). Reflux was continued foran additional 1 h, after which the majority of the solvent was removedin vacuo. The residue was cooled to rt and a mixture of hexanes anddiethyl ether was added. The solid was collected by filtration andwashed with hexanes to give 136D (0.245 g, 46%) as an off-white solid.LC-MS m/z: 359.4 (M+H)⁺.

136E N⁶,N⁶-Dibenzyl-8-fluoroisoquinoline-1,6-diamine

A mixture of 136D (0.284 g, 0.792 mmol) and phosphorous oxychloride (3mL) was heated at 100° C. for 1 h. The reaction mixture was concentratedunder reduced pressure, and ice was added, followed by sodium hydroxide(1N solution) until the pH was basic. The resulting solid was collectedby filtration, washed with water, and dried in vacuo to give a chlorideintermediate (0.33 g) as a yellow solid. A portion of this solid (0.100g) was treated with a saturated solution of ammonia in ethylene glycol(4 mL) at 130° C. in a glass pressure tube overnight. The reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel chromatography (5% methanol/dichloromethane) togive 136E (55 mg, 64%) as a brown solid. LC-MS m/z: 358.4 (M+H)⁺.

136FN⁶,N⁶-Dibenzyl-N¹,N¹-di-tert-butoxycarbonyl-8-fluoroisoquinoline-1,6-diamine

Di-tert-butyl dicarbonate (58 mg, 0.266 mmol) was added to a suspensionof 136E (21 mg, 0.059 mmol) and DMAP (5 mg, 0.041 mmol) in acetonitrile(2 mL). The reaction mixture was stirred overnight at rt and thenconcentrated under reduced pressure. The residue was purified by silicagel chromatography (gradient from 0 to 30% ethyl acetate in hexanes) toafford 136F (23 mg, 70%) as a clear glass. LC-MS m/z: 558.3 (M+H)⁺.

136G N¹,N¹-Di-tert-butoxycarbonyl-8-fluoroisoquinoline-1,6-diamine

A mixture of 136F (77 mg, 0.14 mmol), 20% palladium(II) hydroxide oncarbon (94 mg) and ethanol (20 mL) was hydrogenated (55 psi) for 4 h.The reaction mixture was filtered and concentrated under reducedpressure to give 136G (47 mg, 90%) as a yellow solid. LC-MS m/z: 378.3(M+H)⁺.

136H(1-Di-tert-butoxycarbonylamino-8-fluoro-isoquinolin-6-ylamino)-(3-ethoxy-4-isopropoxy-phenyl)-aceticacid methyl ester

A solution of 136G (66 mg, 0.18 mmol) and methyl2-chloro-2-(3-ethoxy-4-isopropoxyphenyl)acetate (52 mg, 0.18 mmol, seeWO 2004/072101 for synthesis), and N,N-diisopropylethylamine (0.059 mL,0.34 mmol) in dimethylformamide (2 mL) was heated at 90° C. overnight.The reaction mixture was concentrated and the residue was purified bychromatography on silica gel to give 136H (40 mg, 35%). LC-MS m/z: 628.3(M+H)⁺.

136I(1-Di-tert-butoxycarbonylamino-8-fluoro-isoquinolin-6-ylamino)-(3-ethoxy-4-isopropoxy-phenyl)-aceticacid

Lithium hydroxide solution (0.2 mL of 500 mg LiOH in 9.5 mL water) wasadded to a solution of 136H (40 mg, 0.064 mmol) in tetrahydrofuran (1mL) and water (1 mL). After 1 h, the reaction was concentrated underreduced pressure. The residue was partitioned between dichloromethaneand water and acidified with hydrochloric acid (1 N). The organic layerwas dried (MgSO₄) and concentrated under reduced pressure to give 136I(36 mg, 92%) as a yellow glass. LC-MS m/z: 614.3 (M+H)⁺.

136J

Example 136: A solution of 136I (24 mg, 0.039 mmol), Intermediate 7 (19mg, 0.077 mmol), and DIEA (0.020 mL, 0.11 mmol) in DMF (0.5 mL) wastreated with BOP (16 mg, 0.059 mmol). The reaction mixture was stirredovernight at rt and then concentrated under reduced pressure. Theresidue was triturated with water and then purified by silica gelchromatography (gradient from 0 to 100% ethyl acetate in hexanes) toafford 5 mg of di-Boc protected product. This material was dissolved inethyl acetate (1 mL) and treated with hydrogen chloride (1 mL, 4 Nsolution in dioxane). The reaction mixture was stirred overnight at rtand then concentrated under reduced pressure. The residue was purifiedby reverse phase HPLC to afford Example 136 (3.0 mg, 11%) as a whitesolid. LC-MS m/z: 607.3 (M+H)⁺.

Example 137N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-8-fluoro-isoquinolin-6-ylamino)-2-(3-ethoxy-phenyl)-acetamidetrifluoroacetic acid salt

137A2-(1-Di-tert-butoxycarbonylamino-8-fluoroisoquinolin-6-ylamino)-2-(3-ethoxyphenyl)aceticacid

A mixture of 136G (40 mg, 0.11 mmol), 3-ethoxyphenylboronic acid (25 mg,0.15 mmol) and glyoxylic acid monohydrate (15 mg, 0.16 mmol) in1,2-dichloroethane (1 mL) was heated at 100° C. for 10 min in amicrowave reactor. The crude product was purified by reverse phase HPLCto give 137A (22 mg, 36%) as a solid. LC-MS m/z: 556.2 (M+H)⁺.

137B

Example 137: Using the general coupling-deprotection procedure, 137A (22mg, 0.033 mmol) was coupled with Intermediate 9 (22 mg, 0.085 mmol) andsubsequently deprotected to give Example 137 (12 mg, 52%) as a yellowsolid. LC-MS m/z: 594.2 (M+H)⁺.

Example 138N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-8-fluoro-isoquinolin-6-ylamino)-2-(3-ethoxy-phenyl)-N-methyl-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 137A (60 mg, 0.11mmol) was coupled with Intermediate 10 (39 mg, 0.14 mmol) andsubsequently deprotected to give Example 138 (21 mg, 30%) as a yellowsolid. LC-MS m/z: 608.0 (M+H)⁺.

Example 1392-(1-Amino-8-fluoro-isoquinolin-6-ylamino)-N-(2-cyclobutanesulfonyl-benzyl)-2-(3-methoxy-phenyl)-N-methyl-acetamidetrifluoroacetic acid salt

139A2-(1-Di-tert-butoxycarbonylamino-8-fluoroisoquinolin-6-ylamino)-2-(3-methoxyphenyl)aceticacid

A mixture of 136G (106 mg, 0.28 mmol), 3-methoxyphenylboronic acid (52mg, 0.34 mmol) and glyoxylic acid monohydrate (31 mg, 0.34 mmol) in1,2-dichloroethane (2 mL) was heated at 100° C. for 10 min in amicrowave reactor. The crude product was purified by silica gelchromatography (gradient from 0 to 20% methanol in dichloromethane) togive 139A (40 mg, 26%) as a solid. LC-MS m/z: 542.0 (M+H)⁺.

139B

Example 139: Using the general coupling-deprotection procedure, 139A (25mg, 0.046 mmol) was coupled with Intermediate 12 (17 mg, 0.062 mmol) andsubsequently deprotected to give Example 139 (15 mg, 48%) as a yellowsolid. LC-MS m/z: 563.1 (M+H)⁺.

Example 1402-(1-Amino-8-fluoro-isoquinolin-6-ylamino)-N-(2-cyclobutanesulfonyl-benzyl)-2-(3-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 139A (25 mg, 0.046mmol) was coupled with Intermediate 11 (17 mg, 0.065 mmol) andsubsequently deprotected to give Example 140 (19 mg, 62%) as a yellowsolid. LC-MS m/z: 549.1 (M+H)⁺.

Example 141N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-8-fluoro-isoquinolin-6-ylamino)-2-(3-methoxy-phenyl)-N-methyl-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 139A (26 mg, 0.048mmol) was coupled with Intermediate 10 (17 mg, 0.063 mmol) andsubsequently deprotected to give Example 141 (8 mg, 28%) as a yellowsolid. LC-MS m/z: 594.0 (M+H)⁺.

Example 1422-(1-Amino-phthalazin-6-ylamino)-N-(2-cyclobutanesulfonyl-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-methyl-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 134I (45 mg, 0.075mmol) was coupled with Intermediate 12 (27 mg, 0.098 mmol) andsubsequently deprotected to give Example 142 (12 mg, 22%) as a yellowsolid. LC-MS m/z: 618.1 (M+H)⁺.

Example 1432-(1-Amino-phthalazin-6-ylamino)-N-(2-cyclobutanesulfonyl-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 134I (45 mg, 0.075mmol) was coupled with Intermediate 11 (26 mg, 0.10 mmol) andsubsequently deprotected to give Example 143 (12 mg, 22%) as a yellowsolid. LC-MS m/z: 604.2 (M+H)⁺.

Example 1442-(1-Amino-phthalazin-6-ylamino)-N-(2-cyclopropanesulfonyl-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-methyl-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 134 (54 mg, 0.091mmol) was coupled with Intermediate 8 (31 mg, 0.12 mmol) andsubsequently deprotected to give Example 144 (25 mg, 38%) as a solid.LC-MS m/z: 604.1 (M+H)⁺.

Example 1452-(1-Amino-phthalazin-6-ylamino)-N-(2-cyclopropanesulfonyl-benzyl)-2-(4-fluoro-3-methoxy-phenyl)-N-methyl-acetamidetrifluoroacetic acid salt

145A Methyl 2-amino-2-(4-fluoro-3-methoxyphenyl)acetate

Trimethylsilyl cyanide (2 mL, 15 mmol) was added dropwise to a solutionof 4-fluoro-3-methoxybenzaldehyde (1.54 g, 10 mmol) and ammonia (7 N) inmethanol (40 mL) at 0° C. The reaction mixture was stirred at rtovernight and then concentrated under reduced pressure. The residue wasdissolved in methanol (2 mL), cooled to 0° C., and hydrogen chloridesaturated methanol (15 mL) was added. The reaction mixture was heated atreflux overnight, cooled, and then diluted with water and ethyl acetate.The aqueous layer was adjusted to pH 8 with NaOH, and extractedrepeatedly with ethyl acetate. The organic extracts were combined, dried(MgSO₄), and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (10% methanol, 90% chloroform) toafford 145A (0.179 g, 8.4%) as a solid. LC-MS m/z: 197.1 (M−NH₂)⁺.

145B Methyl2-(1-(di-tert-butoxycarbonyl)phthalazin-6-ylamino)-2-(4-fluoro-3-methoxyphenyl)acetate

Using the procedure for preparation of compound 134H, 134G (74 mg, 0.17mmol) was coupled with 145A (60 mg, 0.28 mmol) to give 145B (46 mg, 47%)as a yellow glass. LC-MS m/z: 557.2 (M+H)⁺.

145C2-(1-(Di-tert-butoxycarbonyl)phthalazin-6-ylamino)-2-(4-fluoro-3-methoxyphenyl)aceticacid

Using the procedure for preparation of compound 134I, 145B (46 mg, 0.083mmol) was hydrolyzed to give 145C (30 mg, 67%) as a solid. LC-MS m/z:543.2 (M+H)⁺.

145D

Example 145: Using the general coupling-deprotection procedure, 145C (30mg, 0.055 mmol) was coupled with Intermediate 8 (19 mg, 0.073 mmol) andsubsequently deprotected to give Example 145 (8 mg, 22%) as a whitesolid. LC-MS m/z: 550.2 (M+H)⁺.

Example 146N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-phenyl)-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, Intermediate 16 (54mg, 0.10 mmol) was coupled with Intermediate 9 (33 mg, 0.13 mmol) andsubsequently deprotected to give Example 146 (37 mg, 54%) as a yellowsolid. LC-MS m/z: 576.2 (M+H)⁺.

Example 147N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-methoxy-phenyl)-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 124A (27 mg, 0.051mmol) was coupled with Intermediate 9 (17 mg, 0.066 mmol) andsubsequently deprotected to give Example 147 (23 mg, 66%) as a beigesolid. LC-MS m/z: 562.2 (M+H)⁺.

Example 148N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethyl-phenyl)-acetamidetrifluoroacetic acid salt

148A2-(1-(Di-tert-butoxycarbonyl)isoquinolin-6-ylamino)-2-(3-vinylphenyl)aceticacid

Using the procedure for preparation of Intermediate 16, Intermediate 1(108 mg, 0.300 mmol) was reacted with 3-vinylboronic acid (59 mg, 0.40mmol) and glyoxylic acid monohydrate (38 mg, 0.41 mmol) to give Example148A (60 mg, 38%) as a solid. LC-MS m/z: 520.3 (M+H)⁺.

148B

Example 148: Using the general coupling-deprotection procedure, 148A (26mg, 0.050 mmol) was coupled with Intermediate 9 (17 mg, 0.066 mmol).Prior to deprotection, the material was dissolved in methanol (5 mL) andhydrogenated (60 psi) over 10% palladium/carbon (19 mg) for 2.5 h. Thesolution was filtered and concentrated under reduced pressure. Thismaterial was deprotected according to the general procedure to giveExample 148 (23 mg, 68%) as a beige solid. LC-MS m/z: 560.2 (M+H)⁺.

Example 149N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-methyl-phenyl)-acetamidetrifluoroacetic acid salt

149A2-(1-(Di-tert-butoxycarbonyl)isoquinolin-6-ylamino)-2-(3-methylphenyl)aceticacid

Using the procedure for preparation of Intermediate 16, Intermediate 1(108 mg, 0.300 mmol) was reacted with 3-methylboronic acid (49 mg, 0.36mmol) and glyoxylic acid monohydrate (41 mg, 0.44 mmol)to give Example149A (65 mg, 43%) as a solid. LC-MS m/z: 508.3 (M+H)⁺.

149B

Example 149: Using the general coupling-deprotection procedure, 149A (26mg, 0.051 mmol) was coupled with Intermediate 9 (17 mg, 0.066 mmol) andsubsequently deprotected to give Example 149 as a beige solid. LC-MSm/z: 546.2 (M+H)⁺.

Example 150N-(2-(cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-methoxyphenyl)acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 124A (27 mg, 0.052mmol) was coupled with Intermediate 7 (17 mg, 0.069 mmol) andsubsequently deprotected to give Example 150 (22 mg, 67%) as a yellowsolid. LC-MS m/z: 517.2 (M+H)⁺.

Example 151N-(2-(cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethylphenyl)acetamidetrifluoroacetic acid salt

Using the coupling-hydrogenation-deprotection procedure described forExample 148, 148A (26 mg, 0.050 mmol) was coupled with Intermediate 7(17 mg, 0.069 mmol) and subsequently hydrogenated and deprotected togive Example 151 (13 mg, 41%) as a solid. LC-MS m/z: 515.2 (M+H)⁺.

Example 152N-(2-(cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-methylphenyl)acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 149A (29 mg, 0.057mmol) was coupled with Intermediate 7 (17 mg, 0.069 mmol) andsubsequently deprotected to give Example 152 (29 mg, 83%) as a yellowsolid. LC-MS m/z: 501.2 (M+H)⁺.

Example 153N-(2-(cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxyphenyl)acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, Intermediate 16 (27mg, 0.050 mmol) was coupled with Intermediate 7 (17 mg, 0.069 mmol) andsubsequently deprotected to give Example 153 (12 mg, 37%) as a yellowsolid. LC-MS m/z: 531.2 (M+H)⁺.

Example 154N-(3-Acetylamino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-phenyl)-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, Intermediate 16 (27mg, 0.050 mmol) was coupled with N-(3-(aminomethyl)phenyl)acetamide (18mg, 0.11 mmol) and subsequently deprotected to give Example 154 (9 mg,30%) as a solid. LC-MS m/z: 484.3 (M+H)⁺.

Example 155N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-bromo-phenyl)-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 121D (30 mg, 0.052mmol) was coupled with Intermediate 9 (17 mg, 0.066 mmol) andsubsequently deprotected to give Example 155 (6 mg, 16%) as a beigesolid. LC-MS m/z: 610.1, 612.1 (M+H)⁺.

Example 1562-(1-Amino-isoquinolin-6-ylamino)-2-(3-bromo-phenyl)-N-(2-cyclopropanesulfonyl-benzyl)-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 121D (30 mg, 0.052mmol) was coupled with Intermediate 7 (17 mg, 0.069 mmol) andsubsequently deprotected to give Example 156 (4 mg, 11%) as a whitesolid. LC-MS m/z: 565.0, 567.0 (M+H)⁺.

Example 157N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-chlorophenyl)-acetamidetrifluoroacetic acid salt

157A2-(1-(Di-tert-butoxycarbonyl)isoquinolin-6-ylamino)-2-(3-chlorophenyl)aceticacid

Using the procedure for preparation of Intermediate 16, Intermediate 1(108 mg, 0.300 mmol) was reacted with 3-chloroboronic acid (56 mg, 0.36mmol) and glyoxylic acid monohydrate (36 mg, 0.39 mmol)to give 157A (42mg, 26%) as a solid. LC-MS m/z: 528.2 (M+H)⁺.

157B

Example 157: Using the general coupling-deprotection procedure, 157A (20mg, 0.038 mmol) was coupled with Intermediate 9 (18 mg, 0.070 mmol) andsubsequently deprotected to give Example 157 (16 mg, 62%) as a beigesolid. LC-MS m/z: 566.1, 568.1 (M+H)⁺.

Example 1582-(1-Amino-isoquinolin-6-ylamino)-2-(3-chlorophenyl)-N-(2-cyclopropanesulfonyl-benzyl)-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 157A (20 mg, 0.038mmol) was coupled with Intermediate 7 (16 mg, 0.076 mmol) andsubsequently deprotected to give Example 158 (13 mg, 54%) as a yellowsolid. LC-MS m/z: 521.1, 523.1 (M+H)⁺.

Example 1592-(1-Amino-isoquinolin-6-ylamino)-2-(3-cyclopropylphenyl)-N-(2-cyclopropanesulfonyl-benzyl)-acetamidetrifluoroacetic acid salt

159A(1-Di-tert-Butoxycarbonylamino-isoquinolin-6-ylamino)-(3-cyclopropyl-phenyl)-aceticacid methyl ester

A mixture of 121C (100 mg, 0.17 mmol), cyclopropylboronic acid (30 mg,0.35 mmol), potassium phosphate (150 mg), toluene (2 mL), and water(0.050 mL) was degassed by bubbling N₂ through the suspension.Tricyclohexylphosphine (14 mg) and palladium (II) acetate (7 mg) wasadded and the reaction was heated overnight at 90° C. and thenconcentrated under reduced pressure. The residue was purified by silicagel chromatography (gradient from 0 to 20% methanol in dichloromethane)to give a 2:1 mixture of 159A and 121C (33 mg, 24%) as a clear glass.LC-MS m/z: 548.3 (M+H)⁺.

159B(1-Di-tert-Butoxycarbonylamino-isoquinolin-6-ylamino)-(3-cyclopropyl-phenyl)-aceticacid

Ester 159A (63 mg, 0.1 mmol, 1:1 mixture of 159A and 121C) washydrolyzed according to the procedure for 121D to give a 1:1 mixture159B and 121D as a solid. LC-MS m/z: 534 (M+H)⁺.

159C

Example 159: Using the general coupling-deprotection procedure, 159B (30mg, 0.05 mmol, 1:1 mixture of 159B and 121D) was coupled withIntermediate 7 (24 mg, 0.11 mmol) and subsequently deprotected to giveExample 159 (8 mg) as a beige solid. LC-MS m/z: 527.2 (M+H)⁺.

Example 160N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-cyclopropylphenyl)-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, 159B (30 mg, 0.05mmol, 1:1 mixture of 159B and 121D) was coupled with Intermediate 9 (24mg, 0.094 mmol) and subsequently deprotected to give Example 160 (5 mg)as a beige solid. LC-MS m/z: 572.2 (M+H)⁺.

Example 161N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(4-aminomethyl-3-methyl-phenylamino)-2-(3-ethoxyphenyl)-acetamidetrifluoroacetic acid salt

161A (2-Methyl-4-nitro-benzyl)-carbamic acid tert-butyl ester

Borane (1.5 mL, 1.5 mmol, 1M solution in tetrahydrofuran) was addeddropwise to a solution of 2-methyl-4-nitro-benzonitrile (0.155 g, 0.957mmol) and trimethylborate (1.0 mL, 8.97 mmol) in tetrahydrofuran (5 mL).After 24 h at rt, additional borane solution (1.5 mL) was added and thereaction mixture was heated at 60° C. for 3.5 h. Methanol was addeddropwise at 0° C., and the reaction was concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (3 mL) andtreated with di-tert-butyl dicarbonate (0.240 mL, 1.04 mmol). After 6 hat rt, the reaction mixture was diluted with ethyl acetate and washedwith sodium bicarbonate solution and brine, dried (MgSO₄), andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (gradient from 0 to 20% ethyl acetate in hexanes) togive 161A (0.183 g, 72%) as a colorless oil which solidified onstanding. LC-MS m/z: 555 (2M+Na)⁺.

161B (4-Amino-2-methyl-benzyl)-carbamic acid tert-butyl ester

A solution of 161A (0.306 g, 1.15 mmol) in ethanol (3 mL) washydrogenated (1 atm) over 10% palladium on carbon (15 mg) for 4 h. Thereaction mixture was filtered and concentrated under reduced pressure togive 161B (0.276 g, 100%) as a colorless oil. LC-MS m/z: 181.1(M+H-t-Bu)⁺.

161C2-(4-((tert-butoxycarbonylamino)methyl)-3-methylphenylamino)-2-(3-ethoxyphenyl)aceticacid

Using the procedure for preparation of Intermediate 16, 161B (172 mg,0.728 mmol) was reacted with 3-ethoxyboronic acid (0.147 g, 0.886 mmol)and glyoxylic acid monohydrate (81 mg, 0.88 mmol) to give 161C (140 mg,46%) as a yellow oil. LC-MS m/z: 415.2 (M+H)⁺.

161D

Example 161: Using the general coupling-deprotection procedure, 161C(34.3 mg, 0.083 mmol) was coupled with Intermediate 9 (13.3 mg, 0.051mmol) and subsequently deprotected (using 50% trifluoroacetic acid indichloromethane (1 mL), instead of hydrogen chloride in dioxane/ethylacetate) to give Example 161 (15.7 mg, 45%) as a yellow solid. LC-MSm/z: 536.2 (M−NH₂)⁺.

Example 162N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(4-aminomethyl-phenylamino)-2-(3-ethoxyphenyl)-acetamidetrifluoroacetic acid salt

162A2-(4-((tert-butoxycarbonylamino)methyl)phenylamino)-2-(3-ethoxyphenyl)aceticacid

Using the procedure for preparation of Intermediate 16,4-(N-Boc)-aminomethylaniline (111 mg, 0.500 mmol) was reacted with3-ethoxyboronic acid (0.125 g, 0.75 mmol) and glyoxylic acid monohydrate(55 mg, 0.60 mmol) to give 162A (134 mg, 67%) as an orange oil. LC-MSm/z: 401.3 (M+H)⁺.

162B

Example 162: Using the general coupling-deprotection procedure, 162A (60mg, 0.15 mmol) was coupled with Intermediate 9 (50 mg, 0.195 mmol) andsubsequently deprotected to give Example 162 (45 mg, 61%) as a beigesolid. LC-MS m/z: 522.2 (M−NH₂)⁺.

Example 163N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(4-aminomethyl-3-fluorophenylamino)-2-(3-ethoxyphenyl)-acetamidetrifluoroacetic acid salt

163A (4-Amino-2-fluoro-benzyl)-carbamic acid tert-butyl ester

A solution of 2-fluoro-4-nitrobenzonitrile (0.541 g, 2.43 mmol) inmethanol (20 mL) and hydrochloric acid (3 mL, 6 N) was hydrogenated (55psi) over 10% palladium on carbon (164 mg) overnight. The reactionmixture was filtered and concentrated under reduced pressure. Theresidue was dissolved in tetrahydrofuran (5 mL) and treated with2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.517 mg, 2.10mmol) and triethylamine (0.6 mL, 4.3 mmol). After 16 h at rt, thereaction mixture was diluted with dichloromethane and washed with sodiumbicarbonate solution and brine, dried (MgSO₄), and concentrated underreduced pressure. The residue was purified by silica gel chromatography(gradient from 0 to 50% ethyl acetate in hexanes) to give 1-63A-(0.287g, 60%) as a colorless oil which solidified on standing.

163B2-(4-((tert-butoxycarbonylamino)methyl)-3-fluorophenylamino)-2-(3-ethoxyphenyl)aceticacid

Using the procedure for preparation of Intermediate 16, 163A (120 mg,0.500 mmol) was reacted with 3-ethoxyboronic acid (0.125 g, 0.75 mmol)and glyoxylic acid monohydrate (55 mg, 0.60 mmol) to give 163B (134 mg,64%). LC-MS m/z: 419.3 (M+H)⁺.

163C

Example 163: Using the general coupling-deprotection procedure, 163B (63mg, 0.15 mmol) was coupled with Intermediate 9 (50 mg, 0.195 mmol) andsubsequently deprotected to give Example 163 (36 mg, 36%) as a beigesolid. LC-MS m/z: 540.2 (M−NH₂)⁺.

Example 164N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(4-aminomethyl-3-chlorophenylamino)-2-(3-ethoxyphenyl)-acetamidetrifluoroacetic acid salt

164A (4-Amino-2-chloro-benzyl)-carbamic acid tert-butyl ester

Borane (9 mL, 9 mmol, 1M solution in tetrahydrofuran) was added dropwiseto a solution of 4-amino-2-chlorobenzonitrile (0.500 g, 3.28 mmol) intetrahydrofuran (3 mL) at 0° C. After 2 h at rt, hydrochloric acid (6N)was added slowly dropwise at 0° C., and the reaction was concentratedunder reduced pressure. The residue was dissolved in tetrahydrofuran (5mL) and treated with2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.517 mg, 2.10mmol). After 16 h at rt, the reaction mixture was diluted withdichloromethane and washed with sodium bicarbonate solution and brine,dried (MgSO₄), and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (gradient from 0 to 50% ethylacetate in hexanes) to give 164A (0.427 g, 51%) as a yellow oil whichsolidified on standing.

164B2-(4-((tert-butoxycarbonylamino)methyl)-3-chlorophenylamino)-2-(3-ethoxyphenyl)aceticacid

Using the procedure for preparation of Intermediate 16, 164A (128 mg,0.500 mmol) was reacted with 3-ethoxyboronic acid (0.125 g, 0.75 mmol)and glyoxylic acid monohydrate (55 mg, 0.60 mmol) to give 164B. LC-MSm/z: 435.3 (M+H)⁺.

164C

Example 164: Using the general coupling-deprotection procedure, 164B (32mg, 0.074 mmol) was coupled with Intermediate 9 (25 mg, 0.098 mmol) andsubsequently deprotected to give Example 164 (22 mg, 43%) as a beigesolid. LC-MS m/z: 557.1, 559.1 (M−NH₂)⁺.

Example 165N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(6-aminomethyl-pyridin-3-ylamino)-2-(3-ethoxyphenyl)-acetamidetrifluoroacetic acid salt

165A (6-Cyanopyridin-3-ylamino)-(3-ethoxy-phenyl)-acetic acid

Using the procedure for preparation of Intermediate 16,5-amino-2-cyanopyridine (60 mg, 0.500 mmol) was reacted with3-ethoxyboronic acid (83 mg, 0.50 mmol) and glyoxylic acid monohydrate(55 mg, 0.60 mmol) to give 165A (32 mg, 21%). LC-MS m/z: 298.3 (M+H)⁺.

165BN-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(6-cyanopyridin-3-ylamino)-2-(3-ethoxyphenyl)-acetamide

Using the general coupling-deprotection procedure, 165A (32 mg, 0.11mmol) was coupled with Intermediate 9 (37 mg, 0.14 mmol). The acidicdeprotection step was omitted, to give 165B (40 mg, 68%) as a whitesolid. LC-MS m/z: 536.1 (M+H)⁺.

165C

Example 165: A solution of 165B (0.040 g, 0.075 mmol) in methanol(several mL) was hydrogenated (50 psi) over Raney nickel for 7 h. Thereaction mixture was filtered and concentrated under reduced pressure.The residue was purified by reverse phase HPLC to give Example 165 (25mg, 51%) as a white solid. LC-MS m/z: 540.2 (M+H)⁺.

Example 166N-(5-Acetylamino-2-ethanesulfonylbenzyl)-2-(1-amino-7-fluoro-isoquinolin-6-ylamino)-2-(3-ethoxyphenyl)-N-methyl-acetamidetrifluoroacetic acid salt

166A Ethyl 3-(dibenzylamino)-4-fluorobenzoate

A solution of ethyl-3-amino-4-fluorobenzoate (4.58 g, 25 mmol), benzylbromide (7 mL, 59 mmol), and DIEA (15 mL, 86 mmol) in acetonitrile (50mL) was heated at reflux overnight. An additional portion of benzylbromide (0.5 mL) was added and the reflux was continued 8 h. Thereaction mixture was concentrated under reduced pressure and the residuepurified by silica gel chromatography (gradient from 0 to 10% ethylacetate in hexanes) to give 166A (7.4 g, 81%) as a clear oil thatsolidified on standing.

166B (3-(dibenzylamino)-4-fluorophenyl)methanol

Lithium aluminum hydride (2.5 mL, 1M solution in tetrahydrofuran, 2.5mmol) was added dropwise to a solution of 166A (0.916 g, 2.52 mmol) intetrahydrofuran (10 mL) at 0° C. The reaction mixture was then heated at80° C. for 1.5 h. The mixture was cooled to 0° C. and water (˜1 mL) wasadded dropwise, followed by 1 N NaOH (˜1 mL). The mixture was filtered,the filtrate was concentrated under reduced pressure, and the residuepurified by silica gel chromatography (gradient from 0 to 30% ethylacetate in hexanes) to give 166B (0.9 g, 100%). LC-MS m/z: 322.2 (M+H)⁺.

166C 3-(dibenzylamino)-4-fluorobenzaldehyde

Manganese(IV) oxide (2.3 g, 30 mmol) was added to a solution of 166B(1.4 g, 4.4 mmol) in tetrahydrofuran (35 mL). After two hours, anadditional portion of manganese(IV) oxide (2.3 g) was added. After threehours, the reaction mixture was filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography(gradient from 0 to 30% ethyl acetate in hexanes) to give 166C (0.94 g,68%) together with recovered 166B (0.32 g).

166D (E)-ethyl 3-(3-(dibenzylamino)-4-fluorophenyl)acrylate

Sodium hydride (16 mg, 60% dispersion in oil, 0.4 mmol) was added to asolution of 166C (111 mg, 0.35 mmol) and diethyl phosphoric acid ethylester (94 mg, 0.42 mmol) in tetrahydrofuran (2.5 mL). The reactionmixture was heated at 60° C. for 2 h. The reaction was then diluted withethyl acetate and washed successively with 5% potassium hydrogen sulfatesolution, saturated sodium bicarbonate, water, and brine. The organiclayer was dried (MgSO₄) and concentrated under reduced pressure to give166D (0.122 g, 89%) as an oil that solidified on standing. LC-MS m/z:390.2 (M+H)⁺.

166E (E)-3-(3-(dibenzylamino)-4-fluorophenyl)acrylic acid

Using a procedure similar to that described for 136C, 166D (0.500 g,1.28 mmol) was hydrolyzed to give 166E (0.5 g, 100%) as a white solid.LC-MS m/z: 362.2 (M+H)⁺.

166F 6-(Dibenzylamino)-7-fluoroisoquinolin-1(2H)-one

Using a procedure similar to that described for 136D, 166E (0.500 g,1.38 mmol) was converted to an acyl azide and then cyclized to give 166F(0.22 g, 56%) as an off-white solid. LC-MS m/z: 359.2 (M+H)⁺.

166G N⁶,N⁶-dibenzyl-7-fluoroisoquinoline-1,6-diamine

Using a procedure similar to that described for 136E, 166F (0.22 g, 0.61mmol) was chlorinated and then reacted with ammonia to give 166G as asolid. LC-MS m/z: 358.3 (M+H)⁺.

166HN⁶,N⁶-Dibenzyl-N¹,N¹-di-tert-butoxycarbonyl-7-fluoroisoquinoline-1,6-diamine

A mixture of 166G (50 mg, 0.14 mmol), di-tert-butyl dicarbonate (277 mg,1.27 mmol), and 4-dimethylaminopyridine (6 mg, 0.049 mmol) was heated to130° C. for 15 min. The mixture was concentrated in vacuo, and theresidue was purified by silica gel chromatography (gradient from 0 to500% ethyl acetate in hexanes) to afford 166H (60 mg, 77%) as a solid.LC-MS m/z: 558.2 (M+H)⁺.

166I N¹,N¹-Di-tert-butoxycarbonyl-7-fluoroisoquinoline-1,6-diamine

A mixture of 166H (123 mg, 0.22 mmol), palladium(II) hydroxide on carbon(138 mg, Degussa type) and ethanol (10 mL) was hydrogenated (55 psi) for6 h. The reaction mixture was filtered and concentrated under reducedpressure to give 166I (80 mg, 96%) as a white solid. LC-MS m/z: 378.3(M+H)⁺.

166J(1-Di-tert-butoxycarbonylamino-7-fluoro-isoquinolin-6-ylamino)-(3-ethoxy-phenyl)-aceticacid

Using the procedure for preparation of Intermediate 16, 166I (38 mg,0.10 mmol) was reacted with 3-ethoxyboronic acid (11 mg, 0.30 mmol) andglyoxylic acid monohydrate (22 mg, 0.24 mmol) to give 166J (10 mg, 18%).LC-MS m/z: 556.2 (M+H)⁺.

166K

Example 166: Using the general coupling-deprotection procedure, 166J (10mg, 0.018 mmol) was coupled with Intermediate 10 (10 mg, 0.037 mmol) andsubsequently deprotected to give Example 166 (5 mg, 38%) as a solid.LC-MS m/z: 608.2 (M+H)⁺.

Example 1672-(1-Amino-7-fluoroisoquinolin-6-ylamino)-N-(2-cyclopropanesulfonylbenzyl)-2-(3-ethoxy-4-isopropoxyphenyl)-acetamidetrifluoroacetic acid salt

167A(1-Di-tert-butoxycarbonylamino-7-fluoro-isoquinolin-6-ylamino)-(3-ethoxy-4-isopropoxyphenyl)-aceticacid

Using the procedure for preparation of Intermediate 16, 166I (32 mg,0.085 mmol) was reacted with 3-ethoxy-4-isopropoxyboronic acid (28 mg,0.125 mmol) and glyoxylic acid monohydrate (12 mg, 0.13 mmol) to give167A (32 mg, 61%). LC-MS m/z: 614.2 (M+H)⁺.

167B

Example 167: Using the general coupling-deprotection procedure, 167A (32mg, 0.052 mmol) was coupled with Intermediate 7 (26 mg, 0.10 mmol) andsubsequently deprotected to give Example 167 (15 mg, 40%) as a solid.LC-MS m/z: 607.2 (M+H)⁺.

Example 1683-{[(5-Acetylamino-2-ethanesulfonylbenzylcarbamoyl)-(3-ethoxyphenyl)methyl]amino}benzamidetrifluoroacetic acid salt

168A (3-Carbamoyl-phenylamino)-(3-ethoxy-phenyl)-acetic acid

Using the procedure for preparation of Intermediate 16, 3-aminobenzamide(68 mg, 0.50 mmol) was reacted with 3-ethoxyboronic acid (83 mg, 0.50mmol) and glyoxylic acid monohydrate (55 mg, 0.60 mmol) to give 168A (15mg, 10%) as a white solid. LC-MS m/z: 315.3 (M+H)⁺.

168B

Example 168: Using the general coupling-deprotection procedure, 168A (15mg, 0.048 mmol) was coupled with Intermediate 9 (16 mg, 0.064 mmol) togive Example 168 (20 mg, 62%) as a white solid. LC-MS m/z: 553.2 (M+H)⁺.

Example 169N-(5-Acetylamino-2-ethanesulfonylbenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxyphenyl)-N-methyl-acetamidetrifluoroacetic acid salt

Using the general coupling-deprotection procedure, Intermediate 16 (20mg, 0.056 mmol) was coupled with Intermediate 10 (20 mg, 0.074 mmol) andsubsequently deprotected to give Example 169 (8 mg, 20%) as a whitesolid. LC-MS m/z: 590.2 (M+H)⁺.

Example 170N-(2-Ethylbenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

170A 2-Ethylbenzylamine hydrochloride salt

To 2-ethylbenzonitrile (250 mg, 1.91 mmol) in methanol (19 mL) was added4 M HCl in dioxane (0.57 mL, 2.3 mmol) followed by 10% Pd/C (150 mg).The mixture was hydrogenated (using a hydrogen balloon) for 2 days. Thereaction was filtered through Celite® and concentrated to provide 170Aas a yellow solid (299 mg, 92%). LC-MS: 136.1 (M+H)⁺.

170B

Example 170 (10 mg) was prepared from Intermediate 2 (20 mg) and 170A(7.0 mg) following the general coupling/deprotection procedure in 58%overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.09 (t, J=7.47 Hz, 3H)1.30 (d, J=6.15 Hz, 6H) 1.37 (t, J=6.81 Hz, 3H) 2.54 (q, J=7.62 Hz, 2H)4.01 (q, J=7.03 Hz, 2H) 4.47 (m, 3H) 5.09 (s, 1H) 6.68 (d, J=2.64 Hz,1H) 6.80 (d, J=7.03 Hz, 1H) 6.96 (d, J=7.91 Hz, 1H) 7.12 (m, 7H) 7.32(d, J=7.03 Hz, 1H) 8.08 (d, J=9.23 Hz, 1H) 8.63 (s, 1H). LC-MS: 513.41(M+H)⁺.

Example 171N-(2-(Trifluoromethoxy)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 171 (5.6 mg) was prepared from Intermediate 2 (12 mg) andcommercially available 2-trifluoromethoxybenzylamine (4.6 mg) followingthe general coupling/deprotection procedure in 50% overall yield. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.30 (d, J=6.15 Hz, 6H) 1.37 (t, J=7.03 Hz, 3H)4.02 (q, J=7.03 Hz, 2H) 4.41 (m, 1H) 4.54 (m, 2H) 5.10 (s, 1H) 6.69 (d,J=1.76 Hz, 1H) 6.83 (d, J=7.47 Hz, 1H) 6.97 (d, J=7.91 Hz, 1H) 7.08 (m,1H) 7.13 (m, 3H) 7.20 (m, 2H) 7.31 (m, 2H) 8.08 (d, J=9.23 Hz, 1H) 8.74(s, 1H). LC-MS: 569.36 (M+H)⁺.

Example 172N-(2-Nitrobenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 172 (12 mg) was prepared from Intermediate 2 (30 mg) andcommercially available 2-nitrobenzylamine (13 mg) following the generalcoupling/deprotection procedure in 38% overall yield. LC-MS: 530.09(M+H)⁺

Example 173N-(2-(Phenylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

173A 2-(Phenylsulfonyl)benzonitrile

A mixture of 2-fluorobenzonitrile (1.0 mL, 9.1 mmol) and benzenethiol(1.0 mL, 9.7 mmol) was stirred at 80° C. overnight. The reaction wascooled to rt then concentrated. The residue was dissolved in CH₂Cl₂ (20mL) and cooled to 0° C. MCPBA (˜75%, 4.40 g, 19.1 mmol) was added andthe whole was stirred (0° C. to rt) for 2 h. The reaction was dilutedwith CH₂Cl₂ and was washed with water then brine. The organic layer wasconcentrated then purified via silica gel chromatography eluting with0-30% ethyl acetate/hexane to provide 173A (2.14 g, 90%). LC-MS: 244.11(M+H)⁺

173B 2-(Phenylsulfonyl)benzylamine

To 173A (487 mg, 2.00 mmol) in methanol (10 mL) was added a 4M solutionof HCl in dioxane (0.57 mL, 2.3 mmol) followed by 10% Pd/C (150 mg). Themixture was hydrogenated at 30 psi for 4 h. The reaction was filtered,concentrated and dissolved in ethyl acetate. The solution was washedwith saturated aqueous NaHCO₃. After separation, the organic layer wasconcentrated to provide 173B (350 mg, 71%). LC-MS: 248.1 (M+H)⁺.

173C

Example 173 (10 mg) was prepared from Intermediate 2 (18 mg) and amine173B (25 mg) following the general coupling/deprotection procedure in54% overall yield. LC-MS: 625.35 (M+H)⁺.

Example 174N-(2-(Phenyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 174 (9 mg) was prepared from Intermediate 2 (18 mg) andcommercially available 2-phenylbenzylamine (9.2 mg) following thegeneral coupling/deprotection procedure in 54% overall yield. ¹HNMR-(400 MHz, CD₃OD) δ ppm 1.20 (m, 6H) 1.28 (m, 3H) 3.90 (m, 2H) 4.19(m, 2H) 4.44 (m, 1H) 4.95 (m, 1H) 6.56 (m, 1H) 6.72 (m, 1H) 6.87 (m, 1H)6.94 (m, 1H) 7.00 (m, 1H) 7.16 (m, 12H) 7.98 (d, J=9.23 Hz, 1H) 8.39 (s,1H). LC-MS: 561.39 (M+H)⁺.

Example 175N-(2-(o-Tolyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

175A 2-(o-Tolyl)benzonitrile

2-Cyanophenyl boronic acid (676 mg, 4.60 mmol), 2-bromotoluene (342 mg,2.0 mmol), 3M aqueous sodium carbonate (3 mL), and toluene (18 mL) werecombined in a tube. The mixture was degassed with argon for 3 min, whenpalladium tetrakistriphenylphosphine (230 mg, 0.20 mmol) was added. Thetube was sealed and heated to 100° C. overnight. The reaction was cooledto rt, then concentrated and purified via silica gel chromatographyeluting with 0-10% ethyl acetate/hexanes to provide 175A (113 mg).LC-MS: 194.12 (M+H)⁺

175B 2-(o-Tolyl)benzylamine trifluoroacetic acid salt

To 175A (113 mg, 0.59 mmol) in THF (5 mL) was added a IM THF solution ofBH₃.THF (3.0 mL, 3.0 mmol) and the reaction was heated to reflux for 1h. After cooling to rt, 1M HCl (5 mL) was added, and the reaction washeated to reflux for 10 min. The reaction was cooled to rt, concentratedand purified via preparative HPLC eluting with MeOH/water/TFA to provide175B (135 mg).

175C

Example 175 (3.7 mg) was prepared from Intermediate 2 (30 mg) and 175B(37 mg) following the general coupling/deprotection procedure in 0.5%overall yield. LC-MS: 575.4 (M+H)⁺.

Example 176N-(2-(2-Trifluoromethyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

176A 2-(2-Trifluoromethyl)benzonitrile

2-Trifluoromethyl phenylboronic acid (380 mg, 2.00 mmol),2-bromobenzonitrile (182 mg, 1.0 mmol), potassium carbonate (552 mg,4.00 mmol), dichlorobis(chloro-tert-butylphosphine) palladium (OmniphosCatalysts, Inc.) (54 mg, 0.10 mmol) and methanol (2 mL) were combined ina tube. The tube was sealed and heated to 80° C. for 1 h. The reactionwas cooled to rt, then filtered, concentrated and purified via silicagel chromatography eluting with 0-20% ethyl acetate/hexanes to provide176A (230 mg). LC-MS: 248.03 (M+H)⁺

176B 2-(2-Trifluoromethyl)benzylamine trifluoroacetic acid salt

To 176A (110 mg, 0.45 mmol) in THF (5 mL) was added a 1M THF solution ofBH₃.THF (2.0 mL, 2.0 mmol) and the reaction was refluxed for 1 h. Aftercooling to rt, 1M HCl (5 mL) was added, and the mixture was heated toreflux for 10 min. The reaction was cooled to rt, concentrated andpurified via preparative HPLC (eluting with acetonitrile/water/TFA) toprovide 176B (110 mg). LC-MS: 253.09 (M+H)⁺

176C

Example 176 (7.7 mg) was prepared from Intermediate 2 (24 mg) and 176B(37 mg) following the general coupling/deprotection procedure in 26%overall yield. LC-MS: 629.30 (M+H)⁺.

Example 177N-(2-(m-Tolyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

177A 2-(m-Tolyl)benzonitrile

3-Methyl phenylboronic acid (163 mg, 1.20 mmol), 2-bromobenzonitrile(182 mg, 1.00 mmol), 2M aqueous sodium carbonate (2 mL, 4.00 mmol),dichlorobis(chloro-tert-butylphosphine) palladium (Omniphos Catalysts,Inc.) (180 mg, 0.16 mmol) and toluene (6 mL) were combined in a tube.The mixture was degassed with nitrogen for 2 min, then the tube wassealed and heated to 100° C. for 72 h. The reaction was cooled to rt,diluted with ethyl acetate, washed with water and brine, then dried(Na₂SO₄), filtered and concentrated. The residue was purified via silicagel chromatography eluting with 0-10% ethyl acetate/hexanes to provide177A (156 mg). LC-MS: 194.08 (M+H)⁺

177B 2-(m-Tolyl)benzylamine trifluoroacetic acid salt

To 177A (156 mg, 0.81 mmol) in THF (6 mL) was added a 1M THF solution ofBH₃.THF (6.0 mL, 6.0 mmol) and the solution was refluxed for 2 h. Thereaction was cooled to rt, 1M HCl (5 mL) was added, and the mixture washeated to reflux for 30 min. The reaction was cooled to rt, concentratedand purified via preparative HPLC (eluting with MeOH/water/TFA) toprovide 177B (160 mg). LC-MS: 197.18 (M+H)⁺

177C

Example 177 (2.5 mg) was prepared from Intermediate 2 (20 mg) and 177B(20 mg) following the general coupling/deprotection procedure in 11%overall yield. LC-MS: 575.38 (M+H)⁺.

Example 178N-(2-((2,5-Dimethyl)phenyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

178A 2-((2,5-Dimethyl)phenyl)benzonitrile

2,5-Dimethyl phenylboronic acid (90 mg, 0.60 mmol), 2-bromobenzonitrile(91 mg, 0.50 mmol), 2M sodium carbonate (1.0 mL, 2.00 mmol), palladiumtetrakistriphenylphosphine (58 mg, 0.05 mmol) and toluene (3 mL) werecombined in a tube. The mixture was degassed with nitrogen for 2 min,then was sealed and heated to 85° C. overnight. The reaction was cooledto rt, diluted with ethyl acetate, washed with water and brine, thendried (Na₂SO₄), filtered and concentrated. The residue was purified viasilica gel chromatography eluting with 0-5% ethyl acetate/hexanes toprovide 178A (103 mg). LC-MS: 208.17 (M+H)⁺.

178B 2-((2,5-Dimethyl)phenyl)benzylamine trifluoroacetic acid salt

To 178A (104 mg, 0.50 mmol) in THF (3 mL) was added a 2M THF solution ofBH₃.Me₂S (1.0 mL, 2.0 mmol) and the reaction was refluxed for 1 h. Thesolution was cooled to rt, 1M HCl (1 mL) was added, and the reaction washeated to reflux for 10 min. The mixture was cooled to rt, concentratedand purified via preparative HPLC (eluting with MeOH/water/TFA) toprovide 178B (110 mg). LC-MS: 212.20 (M+H)⁺.

78C

Example 178: To Intermediate 3 (22 mg) in DMF (2 mL) was added EDC (16mg), HOAT (6 mg), 178B (32 mg) and DIPEA (30 μL) and the reaction washeated to 60° C. in a sealed vial for 2 h then at rt overnight. Thereaction was diluted with ethyl acetate and brine. The layers wereseparated and the organic layer was concentrated and purified viapreparative HPLC (eluting with /MeOH/water/TFA) to provide Example 178(12 mg). LC-MS: 589.44 (M+H)⁺.

Example 179N-(2-(Methylthio)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 179 (5.7 mg) was prepared from Intermediate 2 (15 mg) andcommercially available 2-(methylthio)benzylamine (4.8 mg) following thegeneral coupling/deprotection procedure in 42% overall yield. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.30 (d, J=6.15 Hz, 6H) 1.38 (t, J=7.03 Hz, 3H)2.39 (s, 3H) 4.03 (q, J=7.03 Hz, 2H) 4.49 (m, 3H) 5.11 (s, 1H) 6.70 (d,J=2.20 Hz, 1H) 6.83 (d, J=7.03 Hz, 1H) 7.03 (m, 4H) 7.13 (d, J=2.20 Hz,1H) 7.21 (m, 3H) 7.33 (d, J=7.03 Hz, 1H) 8.08 (d, J=9.23 Hz, 1H) 8.61(s, 1H). LC-MS: 531.37 (M+H)⁺.

Example 180N-(2-(2,2,2-trifluoroethylthio)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

180A 2-(2,2,2-Trifluoroethylthio)benzoic acid

To methyl 2-(2,2,2-trifluoroethylthio)benzoate (250 mg, 1.00 mmol) inTHF (5 mL) at 0° C. was added 1M LiOH (1 mL), followed by additional 1MLiOH (1 mL) 1 h later. The reaction was stirred at rt overnight. Thereaction was concentrated, diluted with water (10 mL), and the pH wasadjusted to pH 3 with 1N HCl. The resulting solid was filtered and driedto provide 180A (212 mg).

180B 2-(2,2,2-Trifluoroethylthio)benzamide

To 2-(2,2,2-trifluoroethylthio)benzoic acid (118 mg, 0.50 mmol) in DMF(5 mL) were added EDC (115 mg, 0.60 mmol) and HOBT (81 mg, 0.60 mmol)and the reaction was stirred for 2 h at rt then cooled to 0° C. Ammoniumhydroxide (28%, 0.22 mL, 1.50 mmol) was added, the ice bath was removed,and the reaction was stirred at rt overnight. The reaction wasconcentrated and purified via preparative HPLC to provide 180B (69 mg).LC-MS: 236.14 (M+H)⁺

180C (2-(2,2,2-Trifluoroethylthio)phenyl)methanamine trifluoroaceticacid salt

To 180B (69 mg, 0.29 mmol) in THF (5 mL) was added a IM THF solution ofBH₃.THF (1.5 mL, 1.5 mmol) and the reaction was refluxed for 5 h. Aftercooling to rt, 1M HCl (2 mL) was added, and the mixture was heated toreflux for 1 h. The reaction was cooled to rt, concentrated and purifiedvia preparative HPLC to provide 180C (59 mg). LC-MS: 221.18 (M+H)⁺.

180D

Example 180 (4 mg) was prepared from Intermediate 2 (15 mg) and 180C(7.5 mg) following the general coupling/deprotection procedure in 22%overall yield. LC-MS: 599.41 (M+H)⁺.

Example 181N-(3-Cyanobenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

181A 3-(Azidomethyl)benzonitrile

To a solution of 3-(hydroxymethyl)benzonitrile (1.00 g, 7.50 mmol) inTHF (75 mL) at 0° C. was added DPPA (2.04 mL, 9.00 mmol) followed by DBU(1.23 mL, 8.25 mmol). After stirring at rt overnight, reaction wasconcentrated and purified via silica gel chromatography eluting with 30%ethyl acetate/hexanes to provide 181A (1.60 g) as a clear oil.

181B 3-(Aminomethyl)benzonitrile hydrochloride

To 181A (25 mg, 1.58 mmol) in THF (8 mL) and water (2 mL) was addedpolymer-bound triphenylphospine (0.79 g, ca. 2.37 mmol) and the reactionwas heated to 60° C. for 2 h. After cooling to rt, the reaction wasfiltered and concentrated. The resulting residue was dissolved inacetonitrile, and treated with 4M HCl/dioxane (0.79 mL). The mixture wasconcentrated, diluted with diethyl ether, and filtered to provide 181B(165 mg) as a white solid.

181C

Example 181: To Intermediate 3 (15 mg, 0.035 mmol) in DMF (1 mL) wasadded EDC (10.5 mg, 0.055 mmol), HOAT (6 mg, 0.044 mmol), DIPEA (40 μL,0.23 mmol), and 181B (15 mg, 0.089 mol) and the reaction was heated to60° C. in a sealed vial for 2.5 h. After cooling to rt overnight, thereaction was purified via preparative HPLC (MeOH/water/TFA). The majorpeak was collected and concentrated, then lyophilized(acetonitrile/water) overnight to provide Example 181 (11.5 mg) as ayellow solid. LC-MS: 510.33 (M+H)⁺.

Example 182N-(3-(1H-imidazol-4-yl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

182A 3-(1-Trityl-1H-imidazol-4-yl)benzonitrile

To 3-cyanoboronic acid (100 mg, 0.68 mmol) in DMF (2 mL) in a tube wasadded 4-iodo-1-trityl-1H-imidazole (247 mg, 0.57 mmol), 2M aqueoussodium carbonate (1.7 mL, 3.42 mmol), Pd₂(dba)₃ (21 mg, 0.023 mmol), andtriphenylphosphine (9 mg, 0.034 mmol) and the reaction was degassed withnitrogen for 5 min. The tube was sealed and heated to 80° C. for 6 h,then cooled to rt. The mixture was filtered through Celite® and washedwith ethyl acetate then concentrated. The resulting residue was purifiedvia silica gel chromatography eluting with 10-30% ethyl acetate/hexanesto provide 182A (46 mg).

182B (3-(1H-Imidazol-4-yl)phenyl)methanamine dihydrochloride

To 182A (46 mg, 0.11 mmol) in EtOH (2 mL) was added Pd/C (cat.) and 4MHCl/dioxane (70 μL) and the whole was hydrogenated at 60 psi overnight.The reaction was filtered through Celite® and concentrated to provide amixture of 182B and triphenylmethane (ca. 30 mg). This mixture was takenonto the next step crude.

182C

Example 182 (8 mg) was prepared from Intermediate 2 (20 mg) and 182B (30mg) following the general coupling/deprotection procedure in 29% overallyield. LC-MS: 551.30 (M+H)⁺.

Example 183N-(2-(Methyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 183 (7.3 mg) was prepared from Intermediate 2 (15 mg) andcommercially available 2-(methyl)benzylamine (7.2 mg) following thegeneral coupling/deprotection procedure in 59% overall yield. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.30 (d, J=6.15 Hz, 6H) 1.38 (t, J=7.03 Hz, 3H)2.39 (s, 3H) 4.03 (q, J=7.03 Hz, 2H) 4.49 (m, 3H) 5.11 (s, 1H) 6.70 (d,J=2.20 Hz, 1H) 6.83 (d, J=7.03 Hz, 1H) 7.03 (m, 4H) 7.13 (d, J=2.20 Hz,1H) 7.21 (m, 3H) 7.33 (d, J=7.03 Hz, 1H) 8.08 (d, J=9.23 Hz, 1H) 8.61(s, 1H). LC-MS: 499.3 (M+H)⁺.

Example 184N-(2-(Trifluoromethyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 184 (6.9 mg) was prepared from Intermediate 2 (18 mg) andcommercially available 2-(trifluoromethyl)benzylamine (16 mg) followingthe general coupling/deprotection procedure in 42% overall yield. LC-MS:553.3 (M+H)⁺.

Example 185N-(2-(Ethoxy)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 185 (6.9 mg) was prepared from Intermediate 2 (18 mg) andcommercially available 2-(ethoxy)benzylamine (14 mg) following thegeneral coupling/deprotection procedure in 36% overall yield. LC-MS:529.4 (M+H)⁺.

Example 186N-(2-(Methoxy)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 186 (7.2 mg) was prepared from Intermediate 2 (15 mg) andcommercially available 2-(methoxy)benzylamine (27 mg) following thegeneral coupling/deprotection procedure in 46% overall yield. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.30 (d, J=6.15 Hz, 6H) 1.38 (t, J=7.03 Hz, 3H)2.39 (s, 3H) 4.03 (q, J=7.03 Hz, 2H) 4.45 (m, 3H) 5.11 (m, 1H) 6.70 (d,J=2.20 Hz, 1H) 6.83 (d, J=7.03 Hz, 1H) 7.03 (m, 4H) 7.13 (d, J=2.20 Hz,1H) 7.21 (m, 3H) 7.33 (d, J=7.03 Hz, 1H) 8.08 (d, J=9.23 Hz, 1H) 8.61(s, 1H). LC-MS: 515.4 (M+H)⁺.

Example 187N-(2-(Isopropoxy)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 187 (7.6 mg) was prepared from Intermediate 2 (15 mg) andcommercially available 2-(isopropoxy)benzylamine (33 mg) following thegeneral coupling/deprotection procedure in 46% overall yield. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.18 (d, J=6.15 Hz, 3H) 1.23 (d, J=5.71 Hz, 3H)1.29 (d, J=6.15 Hz, 6H) 1.35 (t, J=7.03 Hz, 3H) 3.97 (m, 2H) 4.39 (m,2H) 4.52 (m, 2H) 5.08 (s, 1H) 6.68 (d, J=2.20 Hz, 1H) 6.73 (t, J=7.47Hz, 1H) 6.81 (d, J=7.03 Hz, 1H) 6.87 (d, J=8.35 Hz, 1H) 6.95 (d, J=7.91Hz, 1H) 7.05 (m, 3H) 7.17 (m, 2H) 7.32 (d, J=7.03 Hz, 1H) 8.08 (d,J=9.23 Hz, 1H) 8.35 (s, 1H). LC-MS: 543.5 (M+H)⁺.

Example 188N-(2-Propoxybenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

188A (2-Propoxyphenyl)methanamine trifluoroacetic acid salt

To commercially available 2-propoxybenzonitrile (161 mg, 1.00 mmol) inTHF (5 mL) was added a 1M THF solution of BH₃.THF (4.00 mL, 4.00 mmol).After heating at reflux for 1 h, the reaction was cooled to rt and 1NHCl (4 mL) was slowly added. The reaction was heated to reflux for 30min, then cooled to rt and concentrated. The resulting residue waspurified via preparative HPLC eluting with MeOH/water/TFA to provide188A (130 mg) as a white solid. LC-MS: 331.21 (2M+H)⁺.

188B

Example 188 (2.1 mg) was prepared from Intermediate 2 (10 mg) and 188A(30 mg) following the general coupling/deprotection procedure in 19%overall yield. LC-MS: 543.3 (M+H)⁺.

Example 189N-(2-Isobutoxybenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

189A 2-Isobutoxybenzonitrile

To 2-hydroxybenzonitrile (60 mg, 0.50 mmol) in DMF (5 mL) in a tube wasadded 1-bromo-2-methylpropane (140 mg, 1.0 mmol) and potassium carbonate(276 mg, 2.0 mmol). The tube was sealed and heated to 95° C. overnight.After cooling to rt, the reaction was diluted with ethyl acetate, washedwith brine, then dried (Na₂SO₄), filtered and concentrated. The residuewas purified via silica gel chromatography eluting with 0-10% ethylacetate/hexanes to provide 189A (78 mg). LC-MS: 176.18 (M+H)⁺.

189B (2-Isobutoxyphenyl)methanamine trifluoroacetic acid salt

189B was prepared from 189A in 100% yield following a procedureanalogous to that used in the preparation of 188A.

189C

Example 189 (3.6 mg) was prepared from Intermediate 2 (24 mg) and 189B(24 mg) following the general coupling/deprotection procedure in 13%overall yield. LC-MS: 557.36 (M+H)⁺.

Example 190N-(2-(Pentan-3-yloxy)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

190A (2-(Pentan-3-yloxy)phenyl)methanamine trifluoroacetic acid salt

190A was prepared from 2-hydroxybenzonitrile in two steps (23% overallyield) following procedures analogous to those used in the preparationof 189B. LC-MS: 194.19 (M+H)⁺.

190B

Example 190: To Intermediate 3 (20 mg) in DMF (1 mL) was added EDC (18mg), HOAT (6 mg), 190A (15 mg) and DIPEA (40 μL) and the reaction washeated to 60° C. in a sealed vial for 2 h. After cooling to rt, thereaction was concentrated and purified via preparative HPLC (elutingwith /MeOH/water/TFA) to provide Example 190 (6.5 mg). LC-MS: 571.38(M+H)⁺.

Example 191N-(2-(Cyclopropylmethoxy)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

191a 2-(Cyclopropylmethoxy)benzonitrile

To 2-hydroxybenzonitrile (119 mg, 1.0 mmol) in acetonitrile (6 mL) wasadded (chloromethyl)cyclopropane (130 mg, 1.4 mmol) and potassiumcarbonate (540 mg, 4.0 mmol), and the reaction was heated to 75° C.overnight. After cooling to rt, the reaction was filtered andconcentrated. The residue was purified via preparative HPLC eluting withMeOH/water/TFA to provide 191A (15 mg). LC-MS: 178.21 (M+H)⁺.

191B (2-(Cyclopropylmethoxy)phenyl)methanamine trifluoroacetic acid salt

191B was prepared from 191A in 48% yield following a procedure analogousto that used in the preparation of 188A.

194C

Example 191 (2.9 mg) was prepared from Intermediate 2 (18 mg) and 191B(11 mg) following the general coupling/deprotection procedure in 14%overall yield. LC-MS: 555.36 (M+H)⁺.

Example 192N-(2-Isopropoxy-3-methylbenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

192A 2-Isopropoxy-3-methylbenzaldehyde

To 2-hydroxy-3-methylbenzaldehyde (680 mg, 5.0 mmol) in DMF (10 mL) wasadded 2-iodopropane (1.70 g, 10.0 mmol) and potassium carbonate (1.04 g,7.5 mmol), and the reaction was heated to 50° C. for 72 h. After coolingto rt, the reaction was diluted with ethyl acetate, washed with water(3×50 mL) and brine (1×50 mL), then dried (Na₂SO₄), filtered andconcentrated. The residue was purified via silica gel chromatographyeluting with 0-10% ethyl acetate/hexanes to provide 192A (840 mg).LC-MS: 201.14 (M+Na)⁺.

192B (2-Isopropoxy-3-methylphenyl)methanol

To 192A (159 mg, 0.9 mmol) in MeOH (5 mL) at 0° C. was added sodiumborohydride (38 mg, 1.0 mmol). The ice bath was removed and the reactionwas stirred for 30 min at rt. The reaction was then concentrated,diluted with ethyl acetate, washed with brine, then the organic layerwas dried (Na₂SO₄), filtered and concentrated. The residue was purifiedvia silica gel chromatography eluting with 0-30% ethyl acetate/hexanesto provide 192B (136 mg). LC-MS: 203.15 (M+Na)⁺.

192C 1-(Azidomethyl)-2-isopropoxy-3-methylbenzene

To 192B (131 mg, 0.73 mmol) in THF (3 mL) at 0° C. was added DPPA (240mg, 0.87 mmol) in THF (0.5 mL) followed by DBU (134 mg, 0.88 mmol) inTHF (0.5 mL). The ice bath was removed and the reaction was stirredovernight. The reaction was then concentrated and purified viapreparative HPLC eluting with MeOH/water/TFA to provide 192C (38 mg).

192D (2-Isopropoxy-3-methylphenyl)methanamine trifluoroacetic acid salt

To 192C (15 mg, 0.073 mmol) in THF (2 mL) and water (1 mL) was addedpolymer-bound triphenylphosphine (50 mg, ˜3.2 mmol/g, ca. 0.16 mmol).The reaction was heated to 60° C. for 1 h, then filtered andconcentrated. The residue was purified via preparative HPLC eluting withMeOH/water/TFA to provide 192D (6 mg). LC-MS: 359.22 (2M+H)⁺.

192E

Example 192 (4.5 mg) was prepared from Intermediate 2 (12 mg) and 192D(6 mg) following the general coupling/deprotection procedure in 34%overall yield. LC-MS: 557.3 (M+H)⁺.

Example 193N-(3-Chloro-2-isopropoxybenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

193A 3-Chloro-2-hydroxybenzonitrile Trifluoroacetic acid salt

193A was prepared from 3-chloro-2-hydroxybenzaldehyde in four steps (6%overall yield) following procedures analogous to those used in thepreparation of 192D. LC-MS: 193.21 (M+H)⁺.

193B

Example 193: To Intermediate 3 (13 mg, 0.03 mmol) in DMF (1.5 mL) wasadded EDC (10 mg, 0.05 mmol), HOAT (3 mg, 0.02 mmol), DIPEA (20 μL, 0.11mmol), and 193A (5 mg, 0.025 mmol) and the reaction was heated to 60° C.in a sealed vial for 4 h. After cooling to rt, the reaction was dilutedwith ethyl acetate and brine. The layers were separated and the organiclayer was concentrated and purified via preparative HPLC (eluting with/MeOH/water/TFA) to provide Example 193 (7 mg). LC-MS: 577.37 (M+H)⁺.

Example 194N-(2-(2-Methylprop-1-enyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

194A 2-(2-Methylprop-1-enyl)benzonitrile

To isopropyl triphenylphosphonium iodide (2.41 g, 5.60 mmol) in THF (5mL) at 0° C. was added 1M potassium tert-butoxide in THF (5.87 mL, 5.87mmol). After stirring for 20 min, 2-cyanobenzaldehyde (500 mg, 3.81mmol) in THF (5.4 mL) was added. After stirring for 30 min at 0° C., thereaction was quenched with saturated aqueous ammonium chloride. Ethylacetate was added and the layers were separated. The organic layer waswashed with water and brine, then dried (MgSO₄), filtered andconcentrated. The resulting residue was purified via silica gelchromatography (0-50% ethyl acetate/hexanes) to provide 194A (211 mg).

194B (2-(2-Methylprop-1-enyl)phenyl)methanamine hydrochloride

To 194A (100 mg, 0.64 mmol) in THF (6 mL) at 0° C. was added 1M LAH inTHF (1.5 mL, 1.50 mmol). After 15 min, the ice bath was removed and thereaction was warmed to rt. After a total of 2 h, the reaction was slowlyquenched with water (0.10 mL) in THF (1 mL), then stirred for 5 min. 15%NaOH (0.3 mL) was added, then after 5 min water (0.3 mL) in THF (1 mL)was added. The mixture was stirred for 5 min then filtered throughCelite®, washing with THF, then concentrated. The resulting residue wasdiluted with diethyl ether and 4M HCl/dioxane (0.20 mL) was added. Theresulting solid was filtered to provide 194B (45 mg) as a grey solid.

194C

Example 194 (9 mg) was prepared from Intermediate 2 (20 mg) and 194B (13mg) following the general coupling/deprotection procedure in 41% overallyield. LC-MS: 539.33 (M+H)⁺.

Example 195N-(2-Isobutylbenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

195A (2-Isobutylphenyl)methanamine hydrochloride

A solution of 194A (40 mg, 0.25 mmol) in MeOH (2 mL) was hydrogenated at60 psi overnight in the presence of Pd(OH)₂/C (cat.) and 4M HCl/dioxane(0.26 mL). The mixture was filtered through Celite® and concentrated toprovide 195A (35 mg) as a white solid. LC-MS: 164.11 (M+H)⁺

195B

Example 195 (9 mg) was prepared from Intermediate 2 (20 mg) and 195A (13mg) following the general coupling/deprotection procedure in 41% overallyield. LC-MS: 541.36 (M+H)⁺.

Example 196N-(2-(Ethylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

196A 2-(Ethylthio)benzonitrile

To 2-bromobenzonitrile (250 mg, 1.37 mmol) in THF (8 mL) at −78° C. wasadded a 1.9M solution of n-BuLi in hexanes (0.80 mL, 1.5 mmol). Afterstirring at the same temperature for 10 min, diethyl disulfide was addedand the reaction was stirred for 15 min. The reaction was quenched withsaturated aqueous ammonium chloride and was allowed to warm to rt. Ethylacetate and water were added and the layers were separated. The organiclayer was washed with brine then was dried (MgSO₄), filtered andconcentrated to provide 196A as a yellow oil (193 mg, 87%). LC-MS:329.25 (2M+H)⁺.

196B 2-(Ethylsulfonyl)benzonitrile

To 196A (193 mg, 1.18 mmol) in CH₂Cl₂ was added 75% MCPBA (817 mg, 3.55mmol). After stirring at rt for 30 min, the reaction was diluted withCH₂Cl₂ and saturated aqueous NaHCO₃. The layers were separated and theorganic layer was washed with saturated aqueous NaHCO₃ and brine, dried(MgSO₄), filtered then concentrated. The resulting residue was purifiedvia preparative HPLC (MeOH/H₂O/TFA) to provide 196B (130 mg, 56%) as ayellow oil. LC-MS: 218.1 (M+23)⁺.

196C (2-(Ethylsulfonyl)benzylamine

To 196B (120 mg, 0.615 mmol) in methanol (10 mL), conc. HCl (100 mg) wasadded followed by 10% Pd/C (10 mg). The mixture was hydrogenated using ahydrogen balloon for 16 h. The mixture was filtered, concentrated anddissolved in ethyl acetate. The solution was washed with saturatedaqueous NaHCO₃ then brine. After separation, the organic layer was dried(Na₂SO₄), filtered, concentrated, and purified via silica getchromatography eluting with 10-40% ethyl acetate/hexanes to providerecovered starting material, 196B (38 mg), and 196C (18 mg, 21%, BORSM).

196D

Example 196 (10 mg) was prepared from Intermediate 2 (18 mg) and amine196C (18 mg) following the general coupling/deprotection procedure in49% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (t, J=7.47 Hz, 3H)1.29 (d, J=6.15 Hz, 6H) 1.36 (t, J=7.03 Hz, 3H) 3.26 (q, J=7.18 Hz, 2H)4.01 (m, 2 H) 4.53 (m, 1H) 4.74 (m, 2H) 5.09 (s, 1H) 6.64 (d, J=2.20 Hz,1H) 6.80 (d, J=7.03 Hz, 1H) 6.96 (d, J=7.91 Hz, 1H) 7.05 (m, 2H) 7.18(dd, J=9.23, 2.64 Hz, 1H) 7.34 (m, 2H) 7.48 (m, 2H) 7.86 (m, 1H) 8.07(d, J=9.23 Hz, 1H) 8.65 (s, 1H). LC-MS: 577.4 (M+H)⁺.

Example 197N-(2-(Isopropylthio)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

197A 2-(Isopropylthio)benzonitrile

To 2-fluorobenzonitrile (605 mg, 5.00 mmol) in DMF (5 mL) in a tube wasadded sodium carbonate (2.12 g, 20.0 mmol) and propane-2-thiol (0.93 mL,10.0 mmol). The tube was sealed and the reaction was heated to 80° C.overnight. After cooling to rt, the reaction was diluted with ethylacetate and water. The layers were separated and the organic layer waswashed with water and brine, then dried (Na₂SO₄), filtered andconcentrated to provide 197A (780 mg). LC-MS: 200.00 (M+Na)⁺.

197B (2-(Isopropylthio)phenyl)methanamine hydrochloride

To 197A (354 mg, 2.00 mmol) in THF (4 mL) was added a 1M THF solution ofBH₃.THF (5.0 mL, 5.0 mmol). After heating at reflux for 2 h, thereaction was cooled to rt and 1 N HCl (5 mL) was slowly added. Thereaction was heated to reflux for 10 min, then cooled to rt andconcentrated. The resulting residue was purified via preparativeHPLCeluting with MeOH/water/TFA to provide 197B (500 mg) as a whitesolid. LC-MS: 182.05 (M+H)⁺.

197C

Example 197 (2.6 mg) was prepared from Intermediate 2 (18 mg) and 197B(30 mg) following the general coupling/deprotection procedure in 13%overall yield. LC-MS: 559.24 (M+H)⁺.

Example 198N-(2-(Isopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 198 (14 mg) was prepared from Intermediate 2 (24 mg) andIntermediate 14 (20 mg) following the general coupling/deprotectionprocedure in 60% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.18 (d,J=7.03 Hz, 3H) 1.23 (d, J=6.59 Hz, 3H) 1.29 (t, J=6.81 Hz, 6H) 1.36 (t,J=7.03 Hz, 3H) 3.45 (m, 1H) 3.99 (m, 2H) 4.53 (m, 1H) 4.74 (m, 2H) 5.09(s, 1H) 6.64 (d, J=2.20 Hz, 1H) 6.80 (d, J=7.03 Hz, 1H) 6.96 (d, J=7.91Hz, 1H) 7.05 (m, 2H) 7.18 (dd, J=9.23, 2.20 Hz, 1H) 7.35 (m, 2H) 7.48(m, 2H) 7.84 (m, 1H) 8.07 (d, J=9.23 Hz, 1H) 8.61 (t, J=6.15 Hz, 1H).LC-MS: 591.43 (M+H)⁺.

Example 199N-(2-(Isobutylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

199A 2-(Isobutylsulfonyl)benzylamine hydrochloride salt

199A (173 mg) was prepared in three steps from 2-bromobenzonitrile (550mg) and diisobutyl disulfide in 23% overall yield following proceduresanalogous to those used in the preparation of Intermediate 14. LC-MS:224.20 (M+H)⁺.

199B

Example 199 (8 mg) was prepared from Intermediate 2 (24 mg) and amine199A (21 mg) following the general coupling/deprotection procedure in28% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.01 (dd, J=6.59, 4.83Hz, 6H) 1.30 (d, J=6.15 Hz, 6H) 1.36 (t, J=6.81 Hz, 3H) 2.17 (m, 1H)3.19 (d, J=6.59 Hz, 2H) 4.00 (m, 2H) 4.53 (m, 1H) 4.74 (m, 2H) 5.10 (s,1H) 6.65 (d, J=2.20 Hz, 1H) 6.80 (d, J=7.03 Hz, 1H) 6.97 (d, J=7.91 Hz,1H) 7.05 (m, 2H) 7.18 (dd, J=9.23, 2.20 Hz, 1H) 7.33 (d, J=7.03 Hz, 2H)7.46 (m, 2H) 7.89 (m, 1H) 8.07 (d, J=9.23 Hz, 1H). LC-MS: 605.4 (M+H)⁺.

Example 200N-(2-(Propylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

200A 2-(Propyl)benzylamine hydrochloride salt

200A was prepared in three steps from 2-bromobenzonitrile anddi-n-propyl disulfide following procedures analogous to those used inthe preparation of Intermediate 14. LC-MS: 210.21 (M+H)⁺.

200B

Example 200 (9 mg) was prepared from Intermediate 2 (18 mg) and 200A (8mg) following the general coupling/deprotection procedure in 43% overallyield. LC-MS: 591.45 (M+H)⁺.

Example 2012-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-(2-ethylsulfamoyl-benzyl)-acetamidetrifluoroacetic acid salt

201A 2-(Aminomethyl)-N-ethylbenzenesulfonamide hydrochloride salt

To 2-cyanobenzene-1-sulfonyl chloride (201 mg, 1.00 mmol) in THF (10mL), a 2M THF solution of ethylamine (5.0 mL, 10.0 mmol) was added.After stirring for 30 min, the reaction was concentrated then purifiedvia preparative HPLC eluting with MeOH/H₂O/TFA to provide2-cyano-N-ethylbenzenesulfonamide (105 mg). The product was dissolved inMeOH (8 mL), conc. HCl (70 mg) was added, and the whole was hydrogenatedat 30 psi for 3 h. The reaction was filtered and dried (Na₂SO₄) toprovide 201A (123 mg, 49%). LC-MS: 215.1 (M+H)⁺.

201B

Example 201 (7 mg) was prepared from Intermediate 2 (18 mg) and 201A (13mg) following the general coupling/deprotection procedure in 33% overallyield. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.98 (t, J=7.03 Hz, 3H) 1.29 (d,J=6.15 Hz, 6H) 1.36 (t, J=7.03 Hz, 3H) 2.79 (q, J=7.47 Hz, 2H) 3.98 (m,2H) 4.52 (m, 1H) 4.78 (m, 2H) 5.08 (s, 1H) 6.64 (d, J=2.20 Hz, 1H) 6.78(d, J=7.47 Hz, 1H) 6.96 (d, J=7.91 Hz, 1H) 7.05 (m, J=10.55, 2.64 Hz,2H) 7.18 (dd, J=9.23, 2.20 Hz, 1H) 7.32 (d, J=7.03 Hz, 2H) 7.40 (m, 2H)7.82 (m, 1H) 8.07 (d, J=9.23 Hz, 1H) 8.64 (t, J=6.15 Hz, 1H). LC-MS:592.5 (M+H)⁺.

Example 2022-(1-Amino-isoquinolin-6-ylamino)-N-(2-dimethylsulfamoyl-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

202A 2-Cyano-N,N-dimethylbenzenesulfonamide

To dimethylamine hydrochloride salt (1.01 g, 12.4 mmol) in water (5 mL),triethylamine (1.70 mL, 12.4 mmol) was added and followed by2-cyanobenzene-1-sulfonyl chloride (500 mg, 2.47 mmol) and THF (1 mL).The reaction was stirred overnight and was then diluted with ethylacetate and water. The layers were separated and the organic layer waswashed with water and brine, then dried (MgSO₄), filtered andconcentrated to provide 202A (335 mg, 65%) as a solid. LC-MS: 211.1(M+H)⁺.

202B 2-(Aminomethyl)-N,N-dimethylbenzenesulfonamide trifluoroacetic acidsalt

To 202A (335 mg, 1.60 mmol) in MeOH (8 mL), 10% Pd/C (170 mg) was addedand followed by 4M solution of HCl in dioxane (1.6 mL, 6.40 mmol) andthe whole was hydrogenated at 60 psi overnight. The reaction wasfiltered through Celite® and concentrated. The resulting residue wasdissolved in EtOAc and water and the layers were separated. The organiclayer was dried (MgSO₄) and concentrated to provide the startingmaterial, 202A (135 mg). The aqueous layer was concentrated and purifiedvia preparative HPLC (MeOH/H₂O/TFA) to provide 202B (99 mg, 32% BORSM).LC-MS: 215.1 (M+H)⁺.

202C

Example 202 (7.9 mg) was prepared from Intermediate 2 (18.0 mg) and 202B(16.0 mg) following the general coupling/deprotection procedure in 45%overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.29 (m, 6H) 1.37 (t,J=6.81 Hz, 3H) 2.74 (s, 6H) 4.02 (m, 2H) 4.54 (m, 1H) 4.76 (m, 2H) 5.11(s, 1H) 6.66 (d, J=2.20 Hz, 1H) 6.81 (d, J=6.59 Hz, 1H) 6.98 (d, J=8.35Hz, 1H) 7.08 (m, 2H) 7.19 (dd, J=9.23, 2.20 Hz, 1H) 7.31 (m, 2H) 7.43(m, 2H) 7.76 (m, 1H) 8.08 (d, J=9.23 Hz, 1H) 8.54 (s, 1H). LC-MS: 592.50(M+H)⁺.

Example 2032-(1-Amino-isoquinolin-6-ylamino)-N-(2-cyclopropylsulfamoyl-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

203A 2-(Aminomethyl)-N-cyclopropylbenzenesulfonamide hydrochloride salt

202A (100 mg) was prepared in two steps from commercially available2-cyanobenzene-1-sulfonyl chloride (201 mg) and cyclopropanamine in 34%overall yield following a procedure analogous to that used in thepreparation of 2-(aminomethyl)-N-ethylbenzenesulfonamide hydrochloridesalt.

203B

Example 203 (9.0 mg) was prepared from Intermediate 2 (18.0 mg) and 203A(16.0 mg) following the general coupling/deprotection procedure in 42%overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.28 (m, 4H) 1.20 (d,J=6.15 Hz, 6H) 1.27 (t, J=7.03 Hz, 3H) 2.05 (m, 1H) 3.89 (m, 2H) 4.43(m, 1H) 4.69 (m, 2H) 5.00 (s, 1H) 6.56 (d, J=2.20 Hz, 1H) 6.71 (d,J=7.03 Hz, 1H) 6.87 (d, J=7.91 Hz, 1H) 6.97 (m, 2H) 7.09 (dd, J=9.01,2.42 Hz, 1H) 7.22 (dd, J=10.55, 7.03 Hz, 2H) 7.32 (m, 2H) 7.80 (m, 1H)7.98 (d, J=9.23 Hz, 1H). LC-MS: 604.5 (M+H)⁺.

Example 2042-(1-Amino-isoquinolin-6-ylamino)-N-(2-cyclohexylsulfamoyl-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

204A 2-(Aminomethyl)-N-cyclohexylbenzenesulfonamide hydrochloride salt

204A (127 mg) was prepared in two steps from commercially available2-cyanobenzene-1-sulfonyl chloride (201 mg) and cyclohexanamine in 42%overall yield following a procedure analogous to that used in thepreparation of 2-(aminomethyl)-N-ethylbenzenesulfonamide hydrochloridesalt. LC-MS: 269.3 (M+H)⁺.

204B

Example 204 (7.3 mg) was prepared from Intermediate 2 (18 mg) and 204A(22 mg) following the general coupling/deprotection procedure in 31%overall yield. LC-MS: 646.4 (M+H)⁺.

Example 2052-(1-Amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-N-(2-isopropylsulfamoyl-benzyl)-acetamidetrifluoroacetic acid salt

205A 2-(Aminomethyl)-N-isopropylbenzenesulfonamide hydrochloride salt

205A (188 mg) was prepared in two steps from commercially available2-cyanobenzene-1-sulfonyl chloride (300 mg) and propan-2-amine in 47%overall yield following a procedure analogous to that used in thepreparation of 2-(aminomethyl)-N-ethylbenzenesulfonamide hydrochloridesalt. LC-MS: 229.26 (M+H)⁺.

205B

Example 205 (9.0 mg) was prepared from Intermediate 2 (18 mg) and 205A(14 mg) following the general coupling/deprotection procedure in 50%overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.88 (dd, J=6.59, 3.95 Hz,6H) 1.20 (d, J=6.15 Hz, 6H) 1.27 (t, J=7.03 Hz, 3H) 3.18 (m, 1H) 3.89(m, 2H) 4.43 (m, 1H) 4.72 (m, 2H) 4.99 (s, 1H) 6.56 (d, J=2.20 Hz, 1H)6.71 (d, J=7.03 Hz, 1H) 6.87 (d, J=7.91 Hz, 1H) 6.97 (m, 2H) 7.09 (dd,J=9.23, 2.20 Hz, 1H) 7.26 (m, 4H) 7.77 (m, 1H) 7.98 (d, J=9.23 Hz, 1H)8.53 (s, 1H). LC-MS: 606.5 (M+H)⁺.

Example 206N-(2-(Morpholinosulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

206A (2-(Morpholinosulfonyl)phenyl)methanamine hydrochloride salt

206A (233 mg) was prepared in two steps from commercially available2-cyanobenzene-1-sulfonyl chloride (201 mg) and morpholine in 91%overall yield following a procedure analogous to that used in thepreparation of 2-(aminomethyl)-N-ethylbenzenesulfonamide hydrochloridesalt.

206B

Example 206 (5.8 mg) was prepared from Intermediate 2 (16 mg) and 206A(12 mg) following the general coupling/deprotection procedure in 35%overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.30 (d, J=6.15 Hz, 6H)1.37 (t, J=7.03 Hz, 3H) 3.06 (m, 4H) 3.66 (t, J=4.61 Hz, 4H) 4.02 (m,2H) 4.54 (m, 1H) 4.74 (m, 2H) 5.12 (s, 1H) 6.67 (d, J=2.20 Hz, 1H) 6.81(d, J=7.03 Hz, 1H) 6.98 (d, J=7.91 Hz, 1H) 7.09 (m, 2H) 7.19 (dd,J=9.23, 2.20 Hz, 1H) 7.31 (m, 2H) 7.43 (m, 2H) 7.80 (m, 1H) 8.08 (d,J=9.23 Hz, 1H) 8.59 (t, J=6.15 Hz, 1H). LC-MS: 634.5 (M+H)⁺.

Example 207N-(2-(Piperidin-1-ylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

207A (2-(Piperidin-1-ylsulfonyl)phenyl)methanamine hydrochloride salt

207A (255 mg) was prepared in two steps from commercially available2-cyanobenzene-1-sulfonyl chloride (201 mg) and piperidine in 88%overall yield following a procedure analogous to that used in thepreparation of 2-(aminomethyl)-N-ethylbenzenesulfonamide hydrochloridesalt.

207B

Example 207 (4.5 mg) was prepared from Intermediate 2 (16 mg) and 207A(12 mg) following the general coupling/deprotection procedure in 23%overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.30 (d, J=6.15 Hz, 6H)1.37 (t, J=6.81 Hz, 3H) 1.53 (m, 6H) 3.07 (m, 4H) 4.01 (m, 2H) 4.53 (m,1H) 4.77 (m, 2H) 5.11 (s, 1H) 6.66 (d, J=2.20 Hz, 1H) 6.81 (d, J=7.03Hz, 1H) 6.97 (d, J=8.35 Hz, 1H) 7.08 (m, 2H) 7.19 (dd, J=9.23, 2.20 Hz,1H) 7.29 (m, 1H) 7.33 (d, J=7.03 Hz, 1H) 7.41 (m, 2H) 7.77 (m, 1H) 8.07(d, J=9.23 Hz, 1H) 8.54 (s, 1H). LC-MS: 632.5 (M+H)⁺.

Example 208(R)-N-(2-(Piperidin-1-ylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt and Example 209

(S)-N-(2-(Piperidin-1-ylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 207 (70 mg) was dissolved in isopropanol and the enantiomerswere separated on a Chiralpak® AD column eluting with 75% heptane, 25%isopropanol, 0.1% DEA which eluted Example 208 (free base), followed byExample 209 (free base). Both products were repurified via preparativeHPLC (MeOH/water/TFA) then lyophilized (acetonitrile/water) overnight toprovide Example 208 (26.0 mg) [LC-MS: 632.38 (M+H)⁺], and Example 209(23.8 mg). [LC-MS: 632.38 (M+H)⁺].

Example 210N-(2-(4-(Trifluoromethyl)piperidin-1-ylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

210A (2-(4-(Trifluoromethyl)piperidin-1-ylsulfonyl)phenyl)methanaminehydrochloride

To 2-cyanobenzene-1-sulfonyl chloride (201 mg, 1.00 mmol) in THF (5 mL),triethylamine (0.84 mL, 6.00 mmol) and 4-trifluoromethylpiperidinehydrochloride (284 mg, 1.50 mmol) were added. After stirring for 2 h,the reaction was concentrated and diluted with ethyl acetate and washedwith water. After drying (Na₂SO₄), filtering, and concentrating, theresidue was purified via silica gel chromatography eluting with 45%ethyl acetate/hexanes to provide2-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)benzonitrile [95 mg, LC-MS:319.19 (M+H)⁺]. The product (52 mg) was dissolved in MeOH (5 mL), conc.HCl (25.0 mg) was added, and the whole was hydrogenated at 50 psiovernight. The reaction was concentrated and purified via preparativeHPLC(CH₃CN/water/TFA) to provide 210A. LC-MS: 323.21 (M+H)⁺.

210B

Example 210 (24 mg) was prepared from Intermediate 2 (20 mg) and 210A(18 mg) following the general coupling/deprotection procedure in 32%overall yield. LC-MS: 700.50 (M+H)⁺.

Example 211N-(2-(4,4-difluoropiperidin-1-ylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

211A (2-(4,4-Difluoropiperidin-1-ylsulfonyl)phenyl)methanaminehydrochloride

(2-(4,4-Difluoropiperidin-1-ylsulfonyl)phenyl)methanamine hydrochloride(81 mg) was prepared in two steps from commercially available2-cyanobenzene-1-sulfonyl chloride (201 mg) and 4,4-difluoropiperidine(316 mg) in 25% overall yield following a procedure analogous to thatused in the preparation 210A. LC-MS: 291.19 (M+H)⁺.

211B

Example 211 (13.2 mg) was prepared from Intermediate 2 (30 mg) and 211A(32 mg) following the general coupling/deprotection procedure in 33%overall yield. LC-MS: 668.45 (M+H)⁺.

Example 212N-(2-(Pyrrolidine-1-carbonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

212A 2-(Pyrrolidine-1-carbonyl)benzonitrile

To 2-cyanobenzoic acid (294 mmol) in acetonitrile (2 mL) were added EDC(460 mg, 2.40 mmol), HOAT (37 mg, 0.27 mmol), and DIPEA (0.70 mL, 4.00mmol) and pyrrolidine (170 mg, 2.40 mmol) and the reaction was stirredat rt overnight. The reaction was concentrated and purified via silicagel chromatography (0-70% ethyl acetate/hexanes) to provide 212A (65mg). LC-MS: 201.24 (M+H)⁺.

212B (2-(Aminomethyl)phenyl)(pyrrolidin-1-yl)methanone trifluoroaceticacid salt

To 212A (65 mg) in MeOH (5 mL) was added Raney-Ni (slurry in water, cat.amount) and the reaction was hydrogenated at 60 psi for 22 h. Thereaction was filtered, concentrated, and purified via preparative HPLCto provide 212B (60 mg). LC-MS: 205.27 (M+H)⁺.

212C

Example 212 (8.4 mg) was prepared from Intermediate 2 (24 mg) and 212B(20 mg) following the general coupling/deprotection procedure in 30%overall yield. LC-MS: 582.48 (M+H)⁺.

Example 213N-(2-(Piperidine-1-carbonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

213A (2-(Aminomethyl)phenyl)(piperidin-1-yl)methanone trifluoroaceticacid salt

213A (49 mg) was prepared in two steps from 2-cyanobenzoic acid andpiperidine in 7% overall yield following procedures analogous to thoseused in the preparation of 212B (with the exception that HOBT was usedinstead of HOAT in the first step). LC-MS: 219.3 (M+H)⁺.

213B

Example 213 (15.7 mg) was prepared from Intermediate 2 (50 mg) and 213A(22 mg) following the general coupling/deprotection procedure in 28%overall yield. LC-MS: 596.43 (M+H)⁺.

Example 214 2-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxyisopropoxy-phenyl)acetamido)methyl)-N,N-dimethylbenzamidetrifluoroacetic acid salt

214A 2-(Aminomethyl)-N,N-dimethylbenzamide trifluoroacetic acid salt

214A (82 mg) was prepared in two steps from 2-cyanobenzoic acid anddimethylamine hydrochloride in 36% overall yield following proceduresanalogous to those used in the preparation of 212B. LC-MS: 179.13(M+H)⁺.

214B

Example 214 (35.6 mg) was prepared from Intermediate 2 (72 mg) and 214A(57 mg) following the general coupling/deprotection procedure in 45%overall yield. LC-MS: 556.45 (M+H)⁺.

Example 2152-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)-N-ethylbenzamidetrifluoroacetic acid salt

215A N-Ethyl-2-(hydroxymethyl)benzamide

To ethylamine hydrochloride (162 mg, 2.00 mmol) in methylene chloride (4mL) at 0° C. was added IM trimethylaluminum in hexane (1.0 mL, 1.0mmol). The ice bath was removed, and after stirring for 20 min,isobenzofuran-1(3H)-one (268 mg, 2.0 mmol) in methylene chloride (3 mL)was added. The mixture was stirred at rt for 2 h, then was heated to 40°C. for 4 h, then at 35° C. overnight. After cooling to rt, the reactionwas diluted with ethyl acetate and water. The layers were separated andthe organic layer was washed with brine, then dried (Na₂SO₄), filteredand concentrated. The residue was purified via silica gel chromatographyeluting with 0-80% ethyl acetate/hexanes to provide 215A (245 mg).LC-MS: 180.18 (M+H)⁺.

215B 2-(Azidomethyl)-N-ethylbenzamide

To 215A (89 mg, 0.50 mmol) in THF (2 mL) at 0° C. was added DPPA (165mg, 0.60 mmol) in THF (0.5 mL) followed by DBU (92 mg, 0.60 mmol) in THF(0.5 mL). The ice bath was removed and the reaction was stirredovernight. The reaction was then concentrated and purified via silicagel chromatography to provide 215B (71 mg).

215C 2-(Aminomethyl)-N-ethylbenzamide trifluoroacetic acid salt

To 215B (40 mg, 0.20 mmol) in THF (2 mL) and water (0.5 mL) was addedtriphenylphosphine (polymer-bound, ˜3.2 mmol/g) (200 mg, ca. 0.60 mmol).The reaction was heated to 50° C. for 1 h, then filtered andconcentrated. The residue was purified via preparative HPLC eluting withMeOH/water/TFA to provide 215C (10 mg). LC-MS: 179.22 (M+H)⁺.

215D

Example 215: To Intermediate 3 (14 mg) in DMF (1 mL) was added EDC (13mg), HOAT (5 mg), 215C (10 mg) and DIPEA (30 μL) and the reaction washeated to 60° C. in a sealed vial for 2 h then stirred at rt overnight.The reaction was concentrated and purified via preparative HPLC (elutingwith /MeOH/water/TFA) to provide Example 215 (4.0 mg). LC-MS: 556.35(M+H)⁺.

Example 2162-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamido)methyl)-N-isopropylbenzamidetrifluoroacetic acid salt

216A 2-(Aminomethyl)-N-isopropylbenzamide trifluoroacetic acid salt

216A was prepared from isobenzofuran-1(3H)-one and isopropylamine inthree steps (9% overall yield) following procedures analogous to thoseused in the preparation of 2-(aminomethyl)-N-ethylbenzamidetrifluoroacetic acid salt. LC-MS: 193.21 (M+H)⁺.

216B

Example 216: To Intermediate 3 (19 mg) in DMF (2 mL) was added EDC (16mg), HOAT (6 mg), 216A (27 mg) and DIPEA (30 μL) and the reaction washeated to 60° C. in a sealed vial for 2 h. After cooling to rt, thereaction was diluted with ethyl acetate and brine. The layers wereseparated and the organic layer was concentrated and purified viapreparative HPLC (eluting with /MeOH/water/TFA) to provide Example 216(12.2 mg). LC-MS: 570.43 (M+H)⁺.

Example 2172-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-acetamido)methyl)-N-methylbenzamidetrifluoroacetic acid salt

217A 2-(Aminomethyl)-N-methylbenzamide trifluoroacetic acid salt

217A was prepared from isobenzofuran-1(3H)-one and methylaminehydrochloride in three steps following procedures analogous to thoseused in the preparation of 2-(aminomethyl)-N-ethylbenzamidetrifluoroacetic acid salt. LC-MS: 165.21 (M+H)⁺.

217B

Example 217: To Intermediate 3 (18 mg) in DMF (1 mL) was added EDC (16.5mg), HOAT (5.4 mg), 217A (24 mg) and DIPEA (30 μL) and the reaction washeated to 60° C. in a sealed vial for 2 h. After cooling to rt, thereaction was diluted with ethyl acetate and brine. The layers wereseparated and the organic layer was concentrated and purified viapreparative HPLC (eluting with /MeOH/water/TFA) to provide Example 217(6.0 mg). LC-MS: 542.33 (M+H)⁺.

Example 218N-(2-(tert-Butylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

218A 2-(tert-Butylsulfonyl)benzonitrile

To 2-fluorobenzonitrile (0.45 mL, 4.13 mmol) in DMF (20 mL) was addedsodium-2-methyl-2-propanethiolate (90%, 617 mg, 4.96 mmol). Afterstirring for 5 min at rt, the reaction was diluted with ethyl acetateand water. The layers were separated and the organic layer was washedwith 1N HCl (3×), water (3×) and brine (1×). The organic layer was thendried (MgSO₄), filtered and concentrated. The resulting residue wasdissolved in CH₂Cl₂ (20 mL) and MCPBA (˜75%, 3.30 g, ca. 14.0 mmol) wasadded. After stirring at rt for 3 h, 1 N NaOH was added and the mixturewas stirred for 10 min. The layers were separated and the organic layerwas washed with 1N NaOH (3×) and brine (1×), then was dried (MgSO₄),filtered and concentrated to provide 218A (812 mg) as a white solid.

218B (2-(tert-Butylsulfonyl)phenyl)methanamine hydrochloride

To 218A (400 mg, 1.79 mmol) in refluxing THF (18 mL), a 2M THF solutionof BH₃.SMe₂ (2.70 mL, 5.37 mmol) was added. After heating at reflux for2 h, the reaction was cooled to rt and 6M HCl (1.00 mL) was slowlyadded. The reaction was heated to reflux for 30 min, then cooled to rt,concentrated and azeotroped (3×) with THF/MeOH on a rotary evaporator.The resulting residue was diluted with THF and filtered to provide 218B(285 mg) as a white solid. LC-MS: 228.13 (M+H)⁺.

218C

Example 218 (5 mg) was prepared from Intermediate 3 (15 mg) and 218B (11mg) following the general coupling/deprotection procedure in 33% overallyield. LC-MS: 605.27 (M+H)⁺.

Example 219N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 219 (183 mg) was prepared from Intermediate 2 (282 mg) andIntermediate 7 (115 mg) following the general coupling/deprotectionprocedure in 66% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.10 (m,4H) 1.29 (t, J=6.59 Hz, 6H) 1.36 (t, J=7.03 Hz, 3H) 2.81 (m, 1H) 4.00(m, 2H) 4.53 (m, 1H) 4.85 (m, 2H) 5.11 (s, 1H) 6.66 (d, J=2.20 Hz, 1H)6.81 (d, J=7.03 Hz, 1H) 6.96 (d, J=8.35 Hz, 1H) 7.06 (m, 2H) 7.18 (dd,J=9.23, 2.64 Hz, 1H) 7.35 (m, 2H) 7.46 (m, 2H) 7.81 (m, 1H) 8.08 (d,J=9.23 Hz, 1H) 8.63 (t, J=6.15 Hz, 1H). LC-MS: 589.40 (M+H)⁺.

Example 220(R)-N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt and Example 221(S)-N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 219 (160 mg) was dissolved in MeOH (13 mL), EtOH (3 mL) andheptane (12 mL) and the enantiomers were separated on a Chiralpak® ADcolumn eluting with 70% heptane, 30% 1:1 MeOH/EtOH, 0.1% DEA whicheluted Example 220 (free base), followed by Example 221 (free base).Both products were repurified via preparative HPLC (MeOH/water/TFA) thenlyophilized (acetonitrile/water) overnight to provide Example 221 (35.2mg) [LC-MS: 589.45 (M+H)⁺], and Example 220 (40.0 mg) [LC-MS: 589.46(M+H)⁺].

Example 222N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamidetrifluoroacetic acid salt

Example 222 (183 mg) was prepared from Intermediate 2 (100 mg) andIntermediate 8 (58 mg) following the general coupling/deprotectionprocedure in 48% overall yield. LC-MS: 603.44 (M+H)⁺.

Example 223(S)-N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamidetrifluoroacetic acid salt and Example 224(R)-N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamidetrifluoroacetic acid salt

Example 222 (75 mg) was dissolved in isopropyl alcohol and theenantiomers were separated on a Chiralpak® AD column eluting with 40%heptane, 60% isopropyl alcohol, 0.1% DEA which eluted Example 223 (freebase), followed by Example 224 (free base). Both products wererepurified via preparative HPLC (MeOH/water/TFA) then lyophilized(acetonitrile/water) overnight to provide Example 223 (31.0 mg) [LC-MS:603.43 (M+H)⁺], and Example 224 (21.0 mg) [LC-MS: 603.42 (M+H)⁺].

Example 225N-(2-(Cyclopropylthio)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

225A 2-(Cyclopropylthio)benzonitrile

To 2,2′-dithio-bis(benzonitrile) (obtained from Sumitomo Seika) (3.00 g,11.2 mmol) in THF (56 mL) at −78° C., a 0.5 M THF solution ofcyclopropyl magnesium bromide (224 mL, 111.9 mmol) was added viaaddition funnel. After 10 min, the reaction was quenched with saturatedaqueous ammonium chloride (200 mL). After warming to rt, the reactionwas diluted with water and ethyl acetate and the layers were separated.The organic layer was washed with water and brine, dried (MgSO₄),filtered and concentrated. The resulting residue was purified via silicagel chromatography eluting with 15% ethyl acetate/hexane to provide 225Aas a yellow oil (2.20 g). LC-MS: 176.02 (M+H)⁺.

225B (2-(Cyclopropylthio)phenyl)methanamine hydrochloride

To 225A (100 mg, 0.57 mmol) in refluxing THF (6 mL), a 2M THF solutionof BH₃.SMe₂ (1.7 mL, 1.71 mmol) was added. After heating at reflux for 1h, the reaction was cooled to rt and 4M HCl (0.51 mL) was slowly added.The reaction was heated to reflux for 1 h, then cooled to rt,concentrated and azeotroped (3×) with THF/MeOH on a rotary evaporator.The resulting residue was taken up in THF and filtered to provide 225B(83 mg) as a yellow solid. LC-MS: 180.14 (M+H)⁺.

225C

Example 225 (8 mg) was prepared from Intermediate 2 (20 mg) and 225B (14mg) following the general coupling/deprotection procedure in 35% overallyield. LC-MS: 557.24 (M+H)⁺.

Example 2262-(1-Amino-isoquinolin-6-ylamino)-N-[2-(benzyl-methyl-sulfamoyl)-benzyl]-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

226A N-Benzyl-2-cyano-N-methylbenzenesulfonamide

To N-methyl-N-benzyl amine (363 mg, 3.00 mmol) in THF (5 mL),triethylamine (505 mg, 5.00 mmol) was added followed by a solution of2-cyanobenzene-1-sulfonyl chloride (201 mg, 1.00 mmol) in THF (5 mL).The reaction mixture was stirred at rt for 30 min. After filtering, themixture was concentrated and purified via silica gelchromatography-(eluting with 30% ethyl acetate/hexane) to provide 226A(120 mg, 42%). LC-MS: 287.22 (M+H)⁺.

226B 2-(Aminomethyl)-N-benzyl-N-methylbenzenesulfonamide hydrochloridesalt

226A (50 mg, 0.175 mmol) was dissolved in MeOH (10 mL), conc. HCl (100mg) was added, and the whole solution was hydrogenated at 50 psiovernight. The mixture was filtered and dried (Na₂SO₄) to provide 226B(46 mg, 79%). LC-MS: 291.25 (M+H)⁺.

226C

Example 226 (4.76 mg) was prepared from Intermediate 2 (15 mg) and 226B(10 mg) following the general coupling/deprotection procedure in 29%overall yield. LC-MS: 668.6 (M+H)⁺.

Example 227N-(2-(Cyclopentylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

227A (2-(Cyclopentylsulfonyl)phenyl)methanamine hydrochloride salt

227A was prepared in three steps from 2,2′-dithio-bis(benzonitrile) (57%overall yield) following procedures analogous to those used in thepreparation of (2-(cyclopropylsulfonyl)phenyl)methanamine hydrochloridesalt. LC-MS: 240.2 (M+H)⁺.

227B

Example 227 (5.4 mg) was prepared from Intermediate 2 (18 mg) and 227A(21 mg) following the general coupling/deprotection procedure in 30%overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.30 (d, J=6.15 Hz, 6H)1.37 (t, J=7.03 Hz, 3H) 1.85 (m, 4H) 3.23 (m, 4H) 4.01 (m, 2H) 4.53 (m,1H) 4.77 (m, 2H) 5.10 (s, 1H) 6.66 (d, J=2.20 Hz, 1H) 6.81 (d, J=7.47Hz, 1H) 6.97 (d, J=8.35 Hz, 1H) 7.07 (m, 2H) 7.18 (dd, J=9.23, 2.20 Hz,1H) 7.30 (m, 2H) 7.41 (m, 2H) 7.79 (m, 1H) 8.07 (d, J=9.23 Hz, 1H) 8.53(t, J=6.15 Hz, 1H). LC-MS: 617.50 (M+H)⁺.

Example 228N-(2-Morpholinobenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 228 (6.3 mg) was prepared from Intermediate 2 (18 mg) andcommercially available 2-morpholinobenzylamine (14 mg) following thegeneral coupling/deprotection procedure in 37% overall yield. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.29 (d, J=6.15 Hz, 6H) 1.35 (t, J=6.81 Hz, 3H)2.90 (m, 4H) 3.78 (t, J=4.39 Hz, 4H) 3.96 (dd, J=7.03, 3.52 Hz, 2H) 4.53(m, 3H) 5.11 (s, 1H) 6.67 (d, J=2.20 Hz, 1H) 6.80 (d, J=7.03 Hz, 1H)6.95 (d, J=7.91 Hz, 1H) 7.12 (m, 8H) 8.09 (d, J=9.23 Hz, 1H). LC-MS:570.50 (M+H)⁺.

Example 229N-(2-(Piperidin-1-yl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 229 (5 mg) was prepared from Intermediate 2 (18 mg) andcommercially available 2-piperidinobenzylamine (14 mg) following thegeneral coupling/deprotection procedure in 25% overall yield. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.27 (d, J=6.11 Hz, 6H) 1.32 (t, J=6.97 Hz, 3H)2.05 (br. s., 2H) 3.51 (br. s., 2H) 3.87 (m, 2H) 4.51 (m, 2H) 4.51 (m,1H) 5.16 (s, 1H) 6.59 (d, J=2.20 Hz, 1H) 6.67 (d, J=7.09 Hz, 1H) 6.93(d, J=8.80 Hz, 1H) 7.01 (m, 2H) 7.20 (dd, J=9.17, 2.32 Hz, 1H) 7.32 (d,J=7.09 Hz, 1H) 7.54 (m, 3H) 7.67 (d, J=8.07 Hz, 1H) 8.10 (d, J=9.29 Hz,1H). LC-MS: 568.50 (M+H)⁺.

Example 230N-(2-(2-Methylpiperidin-1-yl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 230 (9.3 mg) was prepared as a mixture of diastereomers fromIntermediate 2 (18 mg) and commercially available (ART-CHEM)(2-(2-methylpiperidin-1-yl)phenyl)methanamine (14 mg) following thegeneral coupling/deprotection procedure in 55% overall yield. LC-MS582.38 (M+H)⁺.

Example 231N-(2-(3-Methylpiperidin-1-yl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 231 (5 mg) was prepared as a mixture of diastereomers fromIntermediate 2 (18 mg) and commercially available (ART-CHEM)(2-(3-methylpiperidin-1-yl)phenyl)methanamine (14.0 mg) following thegeneral coupling/deprotection procedure in 30% overall yield. LC-MS:582.37 (M+H)⁺.

Example 232N-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 232 (4.2 mg) was prepared from Intermediate 2 (15 mg) andcommercially available (ART-CHEM)(2-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)methanamine hydrochloride (10mg) following the general coupling/deprotection procedure in 29% overallyield. LC-MS: 579.44 (M+H)⁺.

Example 233N-(2-(3,5-Diethyl-1H-pyrazol-1-yl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamideTrifluoroacetic Acid Salt

233A N-(3-Aminobenzyl)-2,2,2-trifluoroacetamide

2-Aminobenzylamine (1.5 Kg, 12.28 mol) was charged to 1.5 L tBME andslurried. Heptanes (13.5 L) were charged to bring the solvent ratio to10% v/v tBME/heptanes. Ethyl trifluoroacetate (1.6 L, 1.9 Kg, 13.5 mol)was added slowly to the reaction at 25±5° C. over 27 min. Visually thisreaction went from a gray or off-white slurry to a bright white slurryof fine crystals. The reaction was stirred for 1 h at ambienttemperature. The product was filtered and washed with 1.2 L of heptanesthen dried by drawing nitrogen through the wet cake overnight to provide233A (2255 g).

233B N-(2-(3,5-Diethyl-1H-pyrazol-1-yl)benzyl)-2,2,2-trifluoroacetamide

To N-(3-aminobenzyl)-2,2,2-trifluoroacetamide (1.00 g, 4.60 mmol) inconc. HCl (9.2 mL) at 0° C. was added sodium nitrite (481 mg, 6.97 mmol)in cold water (4 mL), dropwise. After stirring at the same temperaturefor 30 min, tin (II) chloride dihydrate (3.11 g, 13.8 mmol) in coldconc. HCl (4.5 mL) was slowly added and the ice bath was removed. Afterstirring for 45 min, 2,4-heptadione (1.18 g, 9.20 mmol) and acetonitrile(1 mL) were added. After 1 h, the reaction was filtered through Celite®washing with ethyl acetate and methylene chloride then concentrated. Theresidue was dissolved in ethyl acetate and washed with water (2×) andbrine (1×). The aqueous layer was back-extracted with ethyl acetate, andthe combined organic layers were dried (MgSO₄), filtered andconcentrated. The resulting residue was purified via silica gelchromatography eluting with 0-50% ethyl acetate/hexanes to provide 233B(280 mg) as a yellow oil. LC-MS: 326.09 (M+H)⁺.

233C (2-(3,5-Diethyl-1H-pyrazol-1-yl)phenyl)methanamine

To 233B (140 mg, 0.43 mmol) in MeOH (2 mL) and water (0.30 mL) was addedpotassium carbonate (297 mg, 2.15 mmol) and the reaction was heated to80° C. for 2 h. After cooling to rt, the reaction was concentrated andthe residue was partioned between ethyl acetate and water. The aqueouslayer was back-extracted with ethyl acetate (4×), and the combinedorganic layers were dried (MgSO₄), filtered and concentrated. Theresidue was diluted with diethyl ether and 4M HCl/dioxane (180 μL) wasadded. The resulting solid was filtered, and the hygroscopic solid wascollected by dissolving in MeOH and concentrating to provide 233C (99mg) as a yellow oil.

233D

Example 233 (8 mg) was prepared from Intermediate 2 (20 mg) and 233C (18mg) following the general coupling/deprotection procedure in 29% overallyield. LC-MS: 607.40 (M+H)⁺.

Example 234N-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-hydroxybenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)acetamideTrifluoroacetic Acid Salt

234A Methyl 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methoxybenzoate

To 2-amino-5-methoxy benzoic acid (1.00 g, 5.99 mmol) in conc. HCl (12mL) at 0° C. was added sodium nitrite (496 mg, 7.19 mmol) in cold water(5 mL), dropwise. After stirring at the same temperature for 30 min, tin(II) chloride dihydrate (4.05 g, 18.0 mmol) in cold conc. HCl (6 mL) wasslowly added and the ice bath was removed. After stirring for 45 min,2,4-pentadione (1.23 mL, 12.0 mmol) was added, and after an additional30 min, acetonitrile (3 mL) was added. After 2 h, the reaction wasconcentrated, diluted with methylene chloride, and filtered throughCelite® washing with ethyl acetate and methylene chloride. The solutionwas concentrated and purified via silica gel chromatography eluting with10% MeOH/CH₂Cl₂ to yield a brown solid [6.6 g, LC-MS: 246.98 (M+H)⁺].The solid was dissolved in MeOH (50 mL), cooled to 0° C., and thionylchloride (1.31 mL) was added. After stirring overnight with warming tort, the reaction was heated to reflux all day and overnight. Thereaction was almost complete, and additional thionyl chloride (0.5 mL)was added and reflux continued overnight. After cooling to rt, thereaction was concentrated and purified via silica gel chromatographyeluting with 100% ethyl acetate. The resulting brown oil was dilutedwith ethyl acetate, washed with water, saturated aqueous sodiumbicarbonate (3×), water, and brine (2×). The organic layer was dried(MgSO₄), filtered and concentrated to provide 234A (0.89 g) as a brownoil. LC-MS: 261.08 (M+H)⁺.

234B (2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methoxyphenyl)methanol

To 234A (450 mg, 1.73 mmol) in THF (17 mL) at 0° C. was added 1M LAH inTHF (3.8 mL, 3.80 mmol). After ca. 5 min, the reaction was slowlyquenched with water (0.14 mL) in THF (1 mL), then stirred for 5 min. 15%NaOH (0.4 mL) was added, then after 5 min water (0.4 mL) in THF (1 mL)was added. The mixture was stirred for 5 min then filtered throughCelite®, washing with THF and ethyl acetate. Concentrating provided 234B(393 mg) as a yellow solid. LC-MS: 233.05 (M+H)⁺.

234C 1-(2-(Azidomethyl)-4-methoxyphenyl)-3,5-dimethyl-1H-pyrazole

To 234B (393 mg, 1.70 mmol) in toluene (5 mL) at 0° C. was added DPPA(0.44 mL, 2.04 mmol) followed by DBU (0.28 mL, 1.87 mmol). The ice bathwas removed and the reaction was stirred overnight. The reaction wasthen diluted with water and ethyl acetate, and the layers wereseparated. The organic layer was washed with water and 1 N HCl, thendried (MgSO₄), filtered and concentrated to provide 234C (325 mg) as ayellow oil. LC-MS: 258.01 (M+H)⁺.

234D (2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methoxyphenyl)methanamine

To 234C (325 mg, 1.26 mmol) in THF (13 mL) at 0° C. was added 1M LAH inTHF (1.5 mL, 1.50 mmol). After 45 min, the reaction was slowly quenchedwith water (0.2 mL) in THF (1 mL), then stirred for 5 min. 15% NaOH (0.3mL) was added, then after 5 min water (0.3 mL) in THF (1 mL) was added.The mixture was stirred for 5 min then filtered through Celite®, washingwith THF and ethyl acetate. Concentrating provided 234D (240 mg) as ayellow oil. LC-MS: 232.05 (M+H)⁺.

234E 3-(Aminomethyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)phenol

To 234D (240 mg, 1.04 mmol) in methylene chloride (2.6 mL) at −78° C.was added 1M boron tribromide in methylene chloride (2.6 mL, 2.6 mmol).The cold bath was removed and the reaction was stirred for 2 h, thenplaced in freezer overnight. The reaction was then brought to rt,stirred for 1.5 h then concentrated, diluted with THF and filtered toprovide a solid. The solid was dissolved in water and washed withdiethyl ether (3×). The aqueous layer was basified with 1 N NaOH, thenextracted with diethyl ether/ethyl acetate (3×). The solution was dried(MgSO₄), filtered and concentrated to provide 234E (80 mg) as a whitesolid. LC-MS: 218.15 (M+H)⁺.

234F

Example 234 (5.0 mg) was prepared from Intermediate 4 (20 mg) and 234E(16 mg) following the general coupling/deprotection procedure in 18%overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 2.02 (s, 3H), 2.19 (s, 3H),3.80 (s, 3H), 3.83 (s, 3H), 3.89-4.07 (m, 2H), 5.06 (s, 1H), 6.04 (s,1H), 6.70 (dd, J=18.68, 2.42 Hz, 2H), 6.76 (dd, J=8.35, 2.64 Hz, 1H),6.86 (d, J=7.03 Hz, 1H), 6.96 (d, J=8.35 Hz, 1H), 7.02-7.12 (m, 4H),7.19 (dd, J=9.23, 2.20 Hz, 1H), 7.32 (d, J=7.03 Hz, 1H), 8.09 (d, J=9.23Hz, 1H); LC-MS: 553.14 (M+H)⁺.

Example 235N-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-hydroxybenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamideTrifluoroacetic Acid Salt

Example 235 (7.5 mg) was prepared from Intermediate 2 (20 mg) and 234E(15 mg) following the general coupling/deprotection procedure in 27%overall yield. LC-MS: 595.21 (M+H)⁺.

Example 236N-(2-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamideTrifluoroacetic Acid Salt

236A (2-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanaminehydrochloride

236A was prepared from N-(3-aminobenzyl)-2,2,2-trifluoroacetamide inthree steps (including HCl salt formation) in 42% overall yieldfollowing procedures analogous to those used in the preparation of 233C.

236B

Example 236: To Intermediate 3 (15 mg, 0.035 mmol) in DMF (1 mL) wasadded EDC (10 mg, 0.055 mmol), HOAT (6 mg, 0.044 mmol), DIPEA (40 μL,0.23 mmol) and 236A (32 mg, 0.093 mmol) and the reaction was heated to60° C. in a sealed vial for 2.5 h. After cooling to rt overnight, thereaction was purified via preparative HPLC (MeOH/water/TFA). The majorpeak was collected and concentrated, then lyophilized(acetonitrile/water) overnight to provide Example 236 (13.8 mg) as ayellow solid. LC-MS: 687.34 (M+H)⁺.

Example 237N-(2-(1H-1,2,4-Triazol-1-yl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 237 (12 mg) was prepared from Intermediate 2 (18 mg) andcommercially available (ART-CHEM)(2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine (13 mg) following thegeneral coupling/deprotection procedure in 72% overall yield. LC-MS:552.49 (M+H)⁺.

Example 238N-(2-(N-Methylaminosulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

238A N-tert-Butyl-2-cyano-N-methylbenzenesulfonamide

To N-tert-butylmethylamine (1.50 mL, 12.0 mmol) in THF (7.5 mL) wasadded triethylamine (500 mg, 4.94 mmol) followed by a solution of2-cyanobenzene-1-sulfonyl chloride (600 mg, 3.00 mmol) in THF (3 mL).The reaction mixture was stirred at rt for 30 min. After filtering, thereaction was concentrated and purified via silica gel chromatography(eluting with 25% ethyl acetate/hexane) to provide 238A (150 mg, 20%).LC-MS: 275.19 (M+Na)⁺.

238B 2-(Aminomethyl)-N-tert-butyl-N-methylbenzenesulfonamidehydrochloride salt

Compound 238A (51 mg, 0.202) was dissolved in MeOH (5 mL), conc. HCl (35mg) and 10% Pd/C (cat.) were added, and the mixture was hydrogenated at60 psi for 72 h. The reaction was filtered, concentrated and purifiedvia preparative HPLC eluting with MeOH/water/TFA to provide 238B (17 mg,42%) and recovered 238A (16 mg, 31%).

238C

Example 238 (5.2 mg) was prepared from Intermediate 2 (16 mg) and 238B(16.mg) following the general coupling/deprotection procedure in 33%overall yield (the tert-butyl group was removed in the deprotectionstep). LC-MS: 578.4 (M+H)⁺.

Example 239N-(2-(Azepan-1-ylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

239A (2-(Azepan-1-ylsulfonyl)phenyl)methanamine hydrochloride salt

A (125 mg) was prepared in two steps from 2-cyanobenzene-1-sulfonylchloride (100 mg) and azepane in 82% overall yield following proceduresanalogous to those used in the preparation of2-(aminomethyl)-N-tert-butyl-N-methylbenzenesulfonamide hydrochloridesalt. LC-MS: 269.25 (M+H)⁺.

239B

Example 239 (5.5 mg) was prepared from Intermediate 2 (13 mg) and 239A(12 mg) following the general coupling/deprotection procedure in 39%overall yield. LC-MS: 646.6 (M+H)⁺.

Example 240N-(2-(Pyrrolidin-1-ylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

240A (2-(Pyrrolidin-1-ylsulfonyl)phenyl)methanamine trifluoroacetic acidsalt

240A (210 mg) was prepared in two steps from 2-cyanobenzene-1-sulfonylchloride (260 mg) and pyrrolidine in 40% overall yield followingprocedures analogous to those used in the preparation2-(aminomethyl)-N-tert-butyl-N-methylbenzenesulfonamide hydrochloridesalt followed by purification via preparative HPLC (MeOH/water/TFA).LC-MS: 241.27 (M+H)⁺.

240B

Example 240 (4.6 mg) was prepared from Intermediate 2 (13 mg) and amine240A (16 mg) following the general coupling/deprotection procedure in34% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.30 (d, J=6.15 Hz, 6H)1.37 (t, J=7.03 Hz, 3H) 1.85 (m, 4H) 3.22 (m, 4H) 4.00 (m, 2H) 4.53 (m,1H) 4.76 (m, 2H) 5.10 (s, 1H) 6.66 (d, J=2.20 Hz, 1H) 6.81 (d, J=7.47Hz, 1H) 6.97 (d, J=8.35 Hz, 1H) 7.07 (m, 2H) 7.18 (dd, J=9.23, 2.20 Hz,1H) 7.30 (m, 2H) 7.41 (m, 2H) 7.79 (m, 1H) 8.07 (d, J=9.23 Hz, 1H) 8.54(m, 1H). LC-MS: 618.5 (M+H)⁺.

Example 241N-(2-(Thiomorpholinosulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

241A 2-(Thiomorpholinosulfonyl)benzonitrile

To thiomorpholine (206 mg, 1.99 mmol) in THF (10 mL), triethylamine (300mg, 2.96 mmol) was added and followed by a solution of2-cyanobenzene-1-sulfonyl chloride (100 mg, 0.496 mmol). The reactionmixture was stirred at rt for 20 min. After filtering, the reaction wasconcentrated and purified via silica gel chromatography (eluting with0-30% ethyl acetate/hexane) to provide 241A (78 mg, 58%). LC-MS: 269.2(M+H)⁺.

241B (2-(Thiomorpholinosulfonyl)phenyl)methanamine Hydrochloric AcidSalt

To 241A (74 mg, 0.276 mmol) in THF (3 mL) was added 2M BH₃.SMe₂ in THF(0.10 mL, 1.05 mmol). After heating at reflux for 1 h, the reaction wascooled to rt and 6M HCl (0.20 mL) was added. The reaction mixture washeated to reflux for 30 min, then cooled to rt, concentrated andpurified via preparative HPLC (MeOH/water/TFA) to provide 241B (79 mg,75%). LC-MS: 273.19 (M+H)⁺.

241C

Example 241 (5.3 mg) was prepared from Intermediate 2 (13 mg) and amine241B (16 mg) following the general coupling/deprotection procedure in37% overall yield. ¹H NMR (500 MHz, CD₃OD) δ ppm 1.31 (d, J=6.05 Hz, 6H)1.37 (t, J=6.87 Hz, 3H) 2.64 (dd, J=6.05, 3.85 Hz, 4H) 3.42 (m, 4H) 4.02(m, 2H) 4.54 (m, 1H) 4.73 (m, 2H) 5.12 (s, 1H) 6.68 (d, J=2.20 Hz, 1H)6.83 (d, J=7.15 Hz, 1H) 6.98 (d, J=8.25 Hz, 1H) 7.09 (m, 2H) 7.20 (dd,J=8.80, 2.20 Hz, 1H) 7.27 (m, 1H) 7.33 (d, J=7.15 Hz, 1H) 7.42 (m, 2H)7.79 (m, 1H) 8.08 (d, J=8.80 Hz, 1H) 8.60 (s, 1H). LC-MS: 650.5 (M+H)⁺.

Example 242N-(2-(4-Methylpiperazin-1-ylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

242A (2-(4-Methylpiperazin-1-ylsulfonyl)phenyl)methanamine HydrochloricAcid Salt

242A was prepared in two steps from 2-cyanobenzene-1-sulfonyl chlorideand 1-methylpiperazine in 34% overall yield following proceduresanalogous to those used in the preparation of2-(aminomethyl)-N-tert-butyl-N-methylbenzenesulfonamide hydrochloridesalt. LC-MS: 270.25 (M+H)⁺

242B

Example 242 (5.7 mg) was prepared from Intermediate 2 (13 mg) and 242A(21 mg) following the general coupling/deprotection procedure in 40%overall yield. LC-MS: 647.6 (M+H)⁺.

Example 243N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 243 (33 mg) was prepared from Intermediate 2 (135 mg) andIntermediate 9 (85 mg) following the general coupling/deprotectionprocedure in 20% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07 (t,J=7.25 Hz, 3H) 1.19 (d, J=6.15 Hz, 6H) 1.26 (t, J=7.03 Hz, 3H) 2.03 (s,3H) 3.14 (q, J=7.47 Hz, 2H) 3.87 m, 2H) 4.42 (m, 1H) 4.59 (m, 2H) 4.98(s, 1H) 6.50 (d, J=2.20 Hz, 1H) 6.66 (d, J=7.03 Hz, 1H) 6.85 (d, J=7.91Hz, 1H) 6.94 (m, 2H) 7.07 (dd, J=9.23, 2.20 Hz, 1H) 7.20 (d, J=7.03 Hz,1H) 7.55 (dd, J=8.79, 2.20 Hz, 1H) 7.65 (m, 2H) 7.96 (d, J=9.23 Hz, 1H)8.48 (m, 1H). LC-MS: 634.52 (M+H)⁺.

Example 244N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetamide

Example 244 (10 mg) was prepared from Intermediate 4 (44 mg) andIntermediate 9 (33 mg) following the general coupling/deprotectionprocedure in 18% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07 (t,J=7.25 Hz, 3H) 3.14 (q, J=7.47 Hz, 2H) 3.69 (s, 3H) 3.72 (s, 3H) 4.59(m, 2H) 5.00 (s, 1H) 6.51 (d, J=2.20 Hz, 1H) 6.66 (d, J=7.03 Hz, 1H)6.85 (d, J=8.35 Hz, 1H) 6.97 (m, 2H) 7.07 (dd, J=9.23, 2.20 Hz, 1H) 7.20(d, J=7.03 Hz, 1H) 7.51 (dd, J=8.35, 2.20 Hz, 1H) 7.61 (d, J=1.76 Hz,1H) 7.67 (d, J=8.79 Hz, 1H) 7.96 (d, J=9.23 Hz, 1H) 8.49 (t, J=5.93 Hz,1H). LC-MS: 592.44 (M+H)⁺.

Example 245(R)-N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetamidetrifluoroacetic acid salt and Example 246(S)-N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxy-phenyl)-acetamidetrifluoroacetic acid salt

Example 244 (260 mg) was dissolved in isopropanol and the enantiomerswere separated on a Chiralpak® AD column eluting with 70% heptane, 30%1:1 MeOH/EtOH, 0.1% DEA which eluted Example 245 (free base), followedby Example 246 (free base). Both products were repurified viapreparative HPLC (MeOH/water/TFA) then lyophilized (acetonitrile/water)overnight to provide Example 245 (22.5 mg) [LC-MS: 592.34 (M+H)⁺], andExample 246 (24.8 mg) [LC-MS: 592.31 (M+H)⁺].

Example 247N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)-N-Me-acetamidetrifluoroacetic acid salt

Example 247 (3.1 mg) was prepared from Intermediate 4 (16 mg) andIntermediate 10 (11 mg) following the general coupling/deprotectionprocedure in 16% overall yield. LC-MS: 606.30 (M+H)⁺.

Example 248N-(2-(Ethylsulfonyl)-5-N-aminosulfonylaminobenzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

248A 5-Amino-2-(ethylsulfonyl)benzonitrile

To Intermediate 9B (200 mg, 0.833 mmol) in acetic acid (3.0 mL) wasadded Fe (233 mg, 4.16 mmol). The reaction mixture was heated to 100° C.for 1 h. After cooling to rt, the product was extracted with ethylacetate, and the organic layer was washed with water, then concentratedand azeotroped with toluene to provide 248A (163 mg, 93%) as a tansolid. LC-MS: 209.2 (M−H)⁻.

248B [(3-Cyano-4-ethylsulfonylphenylamino)sulfonyl] carbamic acidphenylmethyl ester

To 248A (163 mg, 0.776 mmol) in CH₂Cl₂ (7 mL) was added benzylchlorosulfonylcarbamate (25A) (232 mg, 0.932 mmol). After stirring at rtfor 3 h, the reaction was concentrated, taken up in ethyl acetate, andwashed with saturated aqueous NaHCO₃ and brine, then dried (MgSO₄),filtered and concentrated to provide 248B (275 mg, 84%) as a yellowfilm. LC-MS: 422.1 (M−H)⁻.

248C 2-Ethylsulfonyl-5-(aminosulfonyl)amino benzylamine hydrochloride

To 248B (275 mg, 0.650 mmol) in MeOH (5 mL), 10% Pd/C (20.0 mg) wasadded. The mixture was hydrogenated at 50 psi for 48 h. The reaction wasconcentrated to provide an off-white solid (219 mg) which contained amixture of 2-ethylsulfonyl-5-aminobenzylamine [LC-MS: 215.27 (M+H)⁺] and248C, 2-ethylsulfonyl-5-(aminosulfonyl)amino benzylamine [LC-MS: 294.24(M+H)⁺].

248D

Example 248: A mixture of Intermediate 2 (44 mg, 0.062 mmol), EDC (24.0mg, 0.13 mmol), HOAT (8.4 mg, 0.062 mmol), DIPEA (54 μL, 0.31 mmol) anda mixture of 2-ethylsulfonyl-5-aminobenzylamine and 248C,2-ethylsulfonyl-5-(aminosulfonyl)amino benzylamine (61 mg) in CH₂Cl₂ (1mL) and DMF (100 μL) was stirred at overnight. The reaction wasconcentrated and purified via preparative HPLC (MeOH/H₂O/TFA) to providetwo products: the first to elute wasN-(2-(ethylsulfonyl)-5-N-aminosulfonylaminobenzyl)-2-(1-bis(tert-butyl)carbonylaminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt [13 mg, LC-MS: 871.65 (M+H)⁺] followed byN-(2-(ethylsulfonyl)-5-N-aminobenzyl)-2-(1-bis(tert-butyl)carbonylaminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt [40 mg, LC-MS: 792.65 (M+H)⁺]. The minorproduct was dissolved in ethyl acetate (0.50 mL) and was treated with 4M HCl in dioxane (0.50 mL) and was stirred at rt overnight. The reactionwas concentrated and purified via preparative HPLC (MeOH/H₂O/TFA) toprovide Example 248 (1.2 mg) as a clear film. ¹H NMR (400 MHz, CD₃OD) δppm 1.06 (t, J=7.25 Hz, 3H) 1.19 (d, J=6.15 Hz, 6H) 1.26 (t, J=7.03 Hz,3H) 3.14 (q, J=7.47 Hz, 2H) 3.86 (m, 2H) 4.42 (m, 1H) 4.59 (m, 2H) 4.98(s, 1H) 6.50 (d, J=2.20 Hz, 1H) 6.66 (d, J=7.03 Hz, 1H) 6.85 (d, J=7.91Hz, 1H) 6.94 (m, 2H) 7.07 (dd, J=9.23, 2.20 Hz, 1H) 7.20 (d, J=7.03 Hz,1H) 7.55 (dd, J=8.79, 2.20 Hz, 1H) 7.65 (m, 2H) 7.96 (d, J=9.23 Hz, 1H)8.48 (t, J=6.15 Hz, 1H). LC-MS: 671.48 (M+H)⁺.

Example 249N-(5-Acetylamino-2-morpholino-benzyl)-2-(1-amino-isoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-acetamide

249A 2-Morpholino-5-nitrobenzonitrile

To 2-fluoro-5-nitrobenzonitrile (1.00 g, 6.02 mmol) in acetonitrile (60mL) was added morpholine (525 μL, 6.02 mmol) and the reaction wasstirred at rt for 1.5 h, then heated to 60° C. Since the reaction wasprogressing slowly, additional morpholine (100 μL) was added and thereaction was heated to 80° C. for 30 min. The reaction was cooled to rt,concentrated, diluted with MeOH and filtered to provide a yellow solid.The filtrate was concentrated, diluted with MeOH, filtered and combinedwith the first lot to provide 249A (1.35 g total) as a yellow solid.

249B N-(3-Cyano-4-morpholinophenyl)acetamide

To 249A (900 mg, 3.86 mmol) in acetic anhydride (9 mL) was added iron(1.08 g, 19.3 mmol) and the reaction was heated to 100° C. for 2 h. Themixture was cooled to rt and poured over ice. When the ice melted, theproduct was extracted with ethyl acetate (2×). The layers were separatedand the organic layer was washed with water (3×), saturated aqueousNaHCO₃ (3×) and brine (1×), then dried (MgSO₄), filtered andconcentrated to provide a yellow solid (200 mg) which contained a 2:1mixture of 249B and the diacylated by-product.

249C N-(3-(Aminomethyl)-4-morpholinophenyl)acetamide trifluoroaceticacid salt

249B (200 mg, 0.816 mmol) was dissolved in MeOH (4 mL) and washydrogenated at 60 psi in the presence of Raney Ni (cat) for 2 d. Themixture was filtered through Celite® and concentrated, and the resultingoil was purified via preparative chromatography eluting withMeOH/water/TFA to provide 249C (108 mg) as a clear oil. LC-MS: 250.10(M+H)⁺.

249D

Example 249 (5.2 mg) was prepared from Intermediate 2 (15 mg) and 249C(20 mg) following the general coupling/deprotection procedure in 25%overall yield. LC-MS: 627.28 (M+H)⁺.

Example 250N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)acetamidetrifluoroacetic acid salt

Example 250 (19 mg) was prepared from Intermediate 4 (33 mg) andIntermediate 7 (23 mg) following the general coupling/deprotectionprocedure in 48% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.09 (m,4H) 2.80 (m, 1H) 3.78 (s, 3H) 3.82 (s, 3H) 4.85 (m, 2H) 5.12 (s, 1H)6.65 (d, J=1.76 Hz, 1H) 6.80 (d, J=7.03 Hz, 1H) 6.96 (m, 1H) 7.09 (m,2H) 7.18 (dd, J=9.23, 2.64 Hz, 1H) 7.34 (m, 2H) 7.46 (m, 2H) 7.80 (m,1H) 8.07 (d, J=9.23 Hz, 1H) 8.64 (t, J=5.93 Hz, 1H). LC-MS: 547.4(M+H)⁺.

Example 251N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)acetamidetrifluoroacetic acid salt

Example 252 (12 mg) was prepared from Intermediate 15 (25 mg) andIntermediate 7 (15 mg) following the general coupling/deprotectionprocedure in 41% overall yield. LC-MS: 604.95 (M+H)⁺.

Example 252N-(2-(Cyclobutylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 252 (32 mg) was prepared from Intermediate 2 (60 mg) andIntermediate 11 (45 mg) following the general coupling/deprotectionprocedure in 45% overall yield. LC-MS: 603.04 (M+H)⁺.

Example 253(R)-N-(2-(Cyclobutylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt and Example 254(S)-N-(2-(Cyclobutylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

Example 252 (46 mg) was dissolved in isopropanol, heptane and DEA andthe enantiomers were separated on a Chiralpak® AD column eluting with60% heptane, 40% isopropanol, 0.1% DEA which eluted Example 253 (freebase), followed by Example 254 (free base). Both products wereseparately dissolved in acetonitrile (˜1 mL) and TFA (˜10 μL) was added.The solutions were concentrated then dissolved in acetonitrile/water andlyophilized overnight to provide Example 253 (20 mg) [LC-MS: 603.24(M+H)⁺], and Example 254 (20 mg) [LC-MS: 603.24 (M+H)⁺].

Example 255N-(2-(Cyclobutylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamidetrifluoroacetic acid salt

Example 255 (32 mg) was prepared from Intermediate 2 (30 mg) andIntermediate 12 (20 mg) following the general coupling/deprotectionprocedure in 23% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.29 (d,J=6.15 Hz, 6H), 1.35 (t, J=7.03 Hz, 3H), 1.85-2.00 (m, 2H), 2.00-2.20(m, 2H), 2.26-2.60 (m, 2H), 3.91-4.04 (m, 2H), 4.08-4.20 (m, 1H),4.47-4.58 (m, 1H), 4.74 (m, 2H), 5.10 (s, 1H), 6.64 (d, J=2.20 Hz, 1H),6.79 (d, J=7.03 Hz, 1H), 6.95-6.98 (m, 1H), 7.01-7.10 (m, 2H), 7.17 (dd,J=9.23, 2.20 Hz, 1H), 7.28-7.39 (m, 2H), 7.39-7.52 (m, 2H), 7.82 (dd,J=7.69, 1.54 Hz, 1H), 8.07 (d, J=9.23 Hz, 1H), 8.63 (t, J=5.93 Hz, 1H);LC-MS: 617.27 (M+H)⁺.

Example 256(R)-N-(2-(Cyclobutylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamidetrifluoroacetic acid salt and Example 257(S)-N-(2-(Cyclobutylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamidetrifluoroacetic acid salt trifluoroacetic acid salt

Example 255 (55 mg) was dissolved in MeOH and the enantiomers wereseparated on a Chiralpak® AD column eluting with 50% heptane, 50% 1:1MeOH/EtOH, 0.1% DEA which eluted Example 256 (free base), followed byExample 257 (free base). Both products were separately dissolved inacetonitrile (0.5 mL) and TFA (˜5 μL) was added. The solutions wereconcentrated then dissolved in acetonitrile/water and lyophilizedovernight to provide Example 256 (23 mg) [LC-MS: 617.19 (M+H)⁺], andExample 257 (23 mg) [LC-MS: 617.17 (M+H)⁺].

Example 258N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-amino-5-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamidetrifluoroacetic acid salt

258A 5-Bromo-6-Amino-1-di-tert-butoxycarbonylaminoisoquinoline

To Intermediate 1 (250 mg, 0.696 mmol) in CH₂Cl₂ (7 mL), NBS (124 mg,0.697 mmol) was added. After stirring for 10 min, the reaction wasconcentrated and purified via silica gel chromatography eluting with30-50% ethyl acetate/hexane to provide 258A (350 mg) as a pale yellowsolid. LC-MS: 438 (M+H)⁺.

258B 5-Methyl-6-Amino-1-di-tert-butoxycarbonylaminoisoquinolinetrifluoroacetic acid salt

258A (150 mg, 0.343 mmol) and PdCl₂(PPh₃)₂ were placed in a tube and thesolids were degassed with nitrogen for 5 min. DMF (1.5 mL) andtetramethyltin (141 mL, 1.02 mmol) were added and the mixture wasdegassed with nitrogen for 2 min. The tube was sealed and the reactionmixture was heated to 110° C. overnight then cooled to rt. The mixturewas loaded onto a silica gel column and was eluted with 100% hexanesfollowed by 30-50% ethyl acetate/hexane. The isolated product waspurified via preparative chromatography (MeOH/water/TFA) to provide 258B(91 mg, 57%) as a yellow film. LC-MS: 374.30 (M+H)⁺.

258C Benzyl2-(1-di-tert-butoxycarbonylamino-5-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetatetrifluoroacetic acid salt

To a mixture of chloro-(3-ethoxy-4-isopropoxy-phenyl)-acetic acid benzylester ((WO 2004072101) (131 mg, 0.361 mmol) and 258B (91 mg, 0.244 mmol)in acetonitrile (2.4 mL) in a tube, DIPEA (167 μL, 0.959 mmol) and TBAB(15 mg, 0.047 mmol) were added. The tube was sealed and the reactionmixture was heated to 80° C. overnight. After cooling to rt, thereaction was concentrated and purified via preparative chromatography(MeOH/water/TFA) to provide benzyl2-(3-ethoxy-4-isopropoxyphenyl)-2-hydroxyacetate (50 mg) followed by258C (43 mg, 26%) as a yellow oil. LC-MS: 700.64 (M+H)⁺.

258D2-(1-Di-tert-butoxycarbonylamino-5-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid trifluoroacetic acid salt

258C (43 mg, 0.062 mmol) in methanol (1 mL) was hydrogenated with ahydrogen balloon in the presence of 10% Pd/C (10 mg) for 1.5 h.Filtration through Celite® and concentration gave compound 258D as ayellow oil (32 mg, 73%). LC-MS: 610.57 (M+H)⁺.

258E

Example 259 (5.1 mg) was prepared from acid 258D (16 mg) andIntermediate 7 (11 mg) following the general coupling/deprotectionprocedure in 35% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.09 (m,4H) 1.29 (d, J=6.15 Hz, 6H) 1.34 (t, J=7.03 Hz, 3H) 2.44 (s, 3H) 2.77(m, 1H) 3.99 (q, J=7.03 Hz, 2H) 4.52 (m, 1H) 4.87 (m, 2H) 5.28 (s, 1H)6.95 (m, 2H) 7.06 (m, 2H) 7.27 (m, 2H) 7.39 (d, J=7.47 Hz, 1H) 7.47 (m,2H) 7.82 (m, 1H) 7.99 (d, J=9.23 Hz, 1H) 8.53 (s, 1H). LC-MS: 603.24(M+H)⁺.

Example 259N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-amino-5-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamidetrifluoroacetic acid salt

Example 259 (6 mg) was prepared from acid 258D (20 mg) and Intermediate8 (17 mg) following the general coupling/deprotection procedure in 25%overall yield. LC-MS: 617.37 (M+H)⁺.

Example 260N-(5-Acetylamino-2-ethanesulfonyl-benzyl)-2-(1-amino-5-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-Me-acetamidetrifluoroacetic acid salt

Example 260 (6 mg) was prepared from 258D (20 mg) and Intermediate 10(18 mg) following the general coupling/deprotection procedure in 23%overall yield. LC-MS: 662.40 (M+H)⁺.

Example 261N-(2-(Cyclopropylsulfonyl)benzyl)-2-(1-amino-5-fluoroisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetamideTrifluoroacetic Acid Salt

261A 5-Fluoro-6-Amino-1-di-tert-butoxycarbonylaminoisoquinoline

To Intermediate 1 (300 mg, 0.836 mg) in acetonitrile (15 mL),Selectfluor™ (296 mg, 0.836 mmol) was added. After stirring for 1 h atrt, the reaction was concentrated and purified via silica gelchromatography eluting with 20-50% ethyl acetate/hexane to provide 261A[88 mg, 28%, LC-MS: 378.33 (M+H)⁺] as a yellow oil followed by thestarting material, 6-amino-1-di-tert-butoxycarbonylaminoisoquinoline(100 mg, 33%).

261B Benzyl2-(1-di-tert-butoxycarbonylamino-5-fluoroisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetateTrifluoroacetic Acid Salt

To a mixture of chloro-(3-ethoxy-4-isopropoxy-phenyl)-acetic acid benzylester (WO 2004072101) (102 mg, 0.281 mmol) and 261A (88 mg, 0.23 mmol)in acetonitrile (2.3 mL) in a tube, DIPEA (160 μl, 0.919 mmol) wasadded. The tube was sealed and the reaction mixture was heated to 80° C.for 16 h. After cooling to rt, the reaction was concentrated andpurified via preparative chromatography (MeOH/water/TFA) to providestarting material, 261A (15.0 mg, 17%) and 261B (88 mg, 47%) as a yellowoil. LC-MS: 704.22 (M+H)⁺.

261C2-(1-Di-tert-butoxycarbonylamino-5-fluoroisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid Trifluoroacetic Acid Salt

261B (88 mg, 0.11 mmol) in methanol (2 mL) was hydrogenated with ahydrogen balloon in the presence of 10% Pd/C (20 mg) for 1.5 h.Filtration through Celite® and concentration gave compound 261C as ayellow glass (77 mg, 98%). LC-MS: 614.17 (M+H)⁺.

261D

Example 261 (9.9 mg) was prepared from acid 261C (28 mg) andIntermediate 7 (19 mg) following the general coupling/deprotectionprocedure in 36% overall yield. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.10 (m,4H) 1.29 (d, J=5.71 Hz, 6H) 1.35 (t, J=7.03 Hz, 3H) 2.79 (m, 1H) 4.00(m, 2H) 4.52 (m, 1H) 4.86 (m, 2H) 5.30 (s, 1H) 6.96 (d, J=7.91 Hz, 1H)7.07 (m, 3H) 7.12 (m, 1H) 7.31 (m, 1H) 7.46 (m, 3H) 7.83 (m, 1H) 7.96(d, J=8.79 Hz, 1H) 8.56 (m, 1H). LC-MS: 607.05 (M+H)⁺.

Example 262N-(2-(Cyclobutylsulfonyl)benzyl)-2-(1-amino-4-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamideTrifluoroacetic Acid Salt

262A N,N-Dibenzyl-3-bromobenzenamine

To 3-bromoaniline (5.00 g, 29.1 mmol) in acetonitrile (145 mL) was addedDIPEA (5.1 mL, 87.2 mmol) and benzyl bromide (7.6 mL, 63.9 mmol) and thereaction was heated to 60° C. overnight. After cooling to rt, thereaction was concentrated and purified via silica gel chromatographyeluting with 100% hexanes−10% ethyl acetate/hexanes to provide 262A(3.85 g) as a yellow oil. LC-MS: 353.92 (M+H)⁺.

262B Methyl 3-(3-(dibenzylamino)phenyl)but-2-enoate

To 262A (3.00 g, 8.52 mmol) in triethylamine (5 mL) in a tube was addedmethyl crotonate (1.8 mL, 17.0 mmol) and the solution was degassed for 5min with nitrogen. Palladium (II) acetate (96.0 mg, 0.43 mmol) andtri(o-tolyl) phosphine (259 mg, 0.85 mmol) were added and degassing wascontinued for another 5 min. The tube was sealed and the reaction washeated to 100° C. for 4 h. After cooling to rt, the reaction was dilutedwith ethyl acetate, filtered through Celite®, concentrated, and purifiedvia silica gel chromatography (eluting with 10% ethyl acetate/hexanes)to provide 262B (1.80 g) as a yellow oil. LC-MS: 372.18 (M+H)⁺.

262C 3-(3-(Dibenzylamino)phenyl)but-2-enoic acid

To 262B (1.8 g, 4.85 mmol) in THF (48 mL) and MeOH (24 mL) was added 1NNaOH (19.4 mL). The reaction was heated to 80° C. for 2.5 h then cooledto rt. The volatiles were removed under reduced pressure, and theremaining solution was cooled to 0° C. and acidified to pH 1 with 1 NHCl. The solution was extracted with ethyl acetate, dried (MgSO₄),filtered and concentrated to provide 262C (1.6 g) as a yellow oil.LC-MS: 358.24 (M+H)⁺.

262D 1-Azido-3-(3-(dibenzylamino)phenyl)but-2-en-1-one

To 262C (800 mg, 2.24 mmol) in acetone (2 mL) at 0° C. was addedtriethylamine (375 μL, 2.69 mmol) and ethylchloroformate (278 μL, 2.91mmol). After stirring for 30 min, sodium azide (218 mg, 3.36 mmol) inwater (1 mL) was added dropwise. The ice bath was removed and thereaction was stirred for 1 h. The reaction was poured over ice, and whenice melted, the acetone was removed under reduced pressure. Theresulting solution was extracted with ethyl acetate, then dried,filtered and concentrated to provide 262D (714 mg) as a yellow oil.LC-MS: 383.09 (M+H)⁺.

262E 6-(Dibenzylamino)-4-methylisoquinolin-1(2H)-one

A solution of 262D (431 mg, 1.13 mmol) in CH₂Cl₂ (2 mL) was added viaaddition funnel to diphenylether (2 mL) and tributylamine (323 mL, 1.36mmol) at 240° C. The CH₂Cl₂ was allowed to evaporate and the reactionwas heated at 240° C. for 2 h. After cooling to rt, hexane was added andthe resulting solid was filtered to provide 262E (244 mg) as a yellowsolid. LC-MS: 355.20 (M+H)⁺.

262F N,N-Dibenzyl-1-chloro-4-methylisoquinolin-6-amine trifluoroacetcacid salt

262E (475 mg, 1.34 mmol) was diluted with phosphorous (III) oxychloride(10 mL) and the reaction was heated to reflux for 1 h. After cooling tort, the reaction was concentrated and purified via flash chromatography(eluting with 30% ethyl acetate/hexanes −100% ethyl acetate −10%MeOH/ethyl acetate) followed by preparative HPLC (MeOH/water/TFA) toprovide 262F (385 mg) as a brown solid. LC-MS: 373.13 (M+H)⁺.

262G 4-Methylisoquinoline-1,6-diamine

262F (295 mg, 0.79 mmol), copper (I) oxide (11 mg, 0.79 mmol) and a −12Msolution of ammonia in ethylene glycol (2.6 mL) were combined in asealed tube and the whole was heated to 130° C. for 62 h. After coolingto rt, the ammonia was removed under reduced pressure and the reactionwas diluted with ethyl acetate, and washed with water and brine. Theaqueous layer was back-extracted with ethyl acetate and the combinedorganic layers were dried (MgSO₄), filtered and concentrated. Theresulting residue was dissolved in MeOH and TFA (10 μL) was added. Thereaction was concentrated and purified via flash chromatography elutingwith 10% MeOH/CH₂Cl₂ to provide 262G (306 mg) as a brown solid. LC-MS:354.01 (M+H)⁺.

262H 4-Me-amino-1-di-tert-butoxycarbonylaminoisoquinoline hydrochloride

A mixture of 262G (150 mg, 0.42 mmol) and di-tert-butyl dicarbonate(324.0 mg, 1.49 mmol) was heated to 130° C. for 30 min. After cooling tort, the residue was purified via silica gel chromatography eluting with30% ethyl acetate/hexanes to provide a yellow foam (128 mg) [LC-MS:554.1 (M+H)⁺]. The foam was dissolved in EtOH (2 mL), Pd(OH)₂/C (ca. 10mg) and 4 M HCl/dioxane (0.23 mL) were added, and the mixture washydrogenated at 50 psi overnight. The reaction was filtered throughCelite® and concentrated to provide 262H (84 mg) as a yellow film.LC-MS: 374.13 (M+H)⁺.

262I Benzyl2-(1-di-tert-butoxycarbonylamino-4-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetate

To a mixture of chloro-(3-ethoxy-4-isopropoxy-phenyl)-acetic acid benzylester (WO 2004072101) (68 mg, 0.187 mmol) and 262H (83 mg, 0.187 mmol)in acetonitrile (2.0 mL) in a tube, DIPEA (130 g, 0.748 mmol) was added.The tube was sealed and the reaction mixture was heated to 80° C.overnight. After cooling to rt, the reaction was concentrated andpurified via silica gel chromatography (50% ethyl acetate/hexanes) toprovide starting material, 262H (18.0 mg) and 262I (33 mg) as a yellowoil. LC-MS: 700.42 (M+H)⁺.

262J Benzyl2-(1-di-tert-butoxycarbonylamino-4-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid

Compound 262I (33 mg, 0.047 mmol) in methanol (2 mL) was hydrogenatedwith a hydrogen balloon in the presence of 10% Pd/C (ca. 10 mg) for 3 h.Filtration through Celite® and concentration provided compound 262J (23mg). LC-MS: 610.11 (M+H)⁺

262K

Example 262 (10 mg) was prepared from 262J (23 mg) and Intermediate 12(26 mg) following the general coupling/deprotection procedure in 29%overall yield. LC-MS: 631.1 (M+H)⁺.

Example 263N-(2-(Cyclobutylsulfonyl)benzyl)-2-(1-amino-7-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-N-methylacetamideTrifluoroacetic Acid Salt

263A N,N-Dibenzyl-5-bromo-2-methylbenzenamine

To 5-bromo-2-methylaniline (5.00 g, 27.0 mmol) in acetonitrile (135 mL)was added DIPEA (14 mL, 81.1 mmol) and benzyl bromide (7.0 mL, 59.4mmol) and the reaction was heated to 65° C. overnight. After cooling tort, the reaction was concentrated and purified via silica gelchromatography eluting with 5% ethyl acetate/hexanes to provide 263A(6.10 g) as a yellow oil.

263B (E)-Methyl 3-(3-(dibenzylamino)-4-methylphenyl)acrylate

To 263A (3.00 g, 8.20 mmol) in triethylamine (4.8 mL) in a tube wasadded methyl acrylate (1.5 mL, 16.4 mmol) and the solution was degassedfor 5 min with nitrogen. Palladium (II) acetate (92.0 mg, 0.41 mmol) andtri(o-tolyl) phosphine (250 mg, 0.82 mmol) were added and degassing wascontinued for another 5 min. The tube was sealed and the reaction washeated to 100° C. for 5.5 h. After cooling to rt, the reaction wasdiluted with ethyl acetate, filtered through Celite®, concentrated, andpurified via silica gel chromatography (eluting with 5-10% ethylacetate/hexanes) to provide 263B (2.8 g) as a clear oil. LC-MS: 372.11(M+H)⁺.

263C (E)-3-(3-(dibenzylamino)-4-methylphenyl)acrylic acid

To 263B (2.8 g, 7.55 mmol) in THF (76 mL) and MeOH (38 mL) was added 1NNaOH (30 mL). The reaction was heated to 80° C. for 1.25 h then cooledto rt. The volatiles were removed under reduced pressure, and theremaining solution was cooled to 0° C. and acidified to pH 1 with 1 NHCl. The solution was extracted with ethyl acetate, dried (MgSO₄),filtered and concentrated to provide 263C (2.59 g) as a yellow solid.LC-MS: 358.11 (M+H)⁺.

263D Benzyl2-(1-di-tert-butoxycarbonylamino-7-methylisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)aceticacid

263D was prepared in 7 steps from 263C following procedures analogous tothose used to prepare 262J. LC-MS: 610.15 (M+H)⁺.

263E

Example 263 (3.0 mg) was prepared from 263D (20 mg) and Intermediate 12(15 mg) following the general coupling/deprotection procedure in 29%overall yield. LC-MS: 631.1 (M+H)⁺.

Example 264N-Benzyl-2-(3-ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)acetamideTrifluoroacetic Acid Salt

A mixture of Intermediate 13 (24 mg, 0.063 mmol), benzylamine (13 mg,0.12 mmol), EDC (23 mg, 0.12 mmol), HOAT (2.5 mg, 0.018 mmol), and DIPEA(24 mg, 0.18 mmol) in CH₂Cl₂/DMF (2 mL, 4:1) was stirred at rtovernight. The reaction was concentrated and purified via preparativeHPLC (MeOH/H₂O/TFA) to provide Example 264 (21 mg, 71%) as a yellowsolid. ¹H NMR (400 MHz, d₆-DMSO) δ ppm 1.22 (d, J=6.15 Hz, 6H) 1.30 (t,J=7.03 Hz, 3H) 3.97 (q, J=6.88 Hz, 2H) 4.31 (m, 2H) 4.47 (m, 1H) 5.26(m, 1H) 6.78 (s, 1H) 6.94 (d, J=8.35 Hz, 1H) 7.03 (m, 1H) 7.19 (m, 5H)7.59 (d, J=8.35 Hz, 1H) 7.76 (d, J=7.03 Hz, 1H) 8.08 (d, J=9.23 Hz, 1H)8.23 (m, 2H) 8.90 (s, 1H) 9.20 (s, 1H). LC-MS: 470.38 (M+H)⁺.

Example 2652-(3-Ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)-N-(2-phenylpropan-2-yl)acetamideTrifluoroacetic Acid Salt

A mixture of Intermediate 13 (23 mg, 0.060 mmol), 2-phenylpropan-2-amine(11 mg, 0.078 mmol), EDC (23 mg, 0.12 mmol), HOAT (2.5 mg, 0.018 mmol),and DIPEA (24 mg, 0.18 mmol) in CH₂Cl₂/DMF (2 mL, 4:1) was stirred at rtovernight. The reaction was concentrated and purified via preparativeHPLC (MeOH/H₂O/TFA) to provide Example 265 (18 mg, 60%) as a yellowsolid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.27 (m, 6H) 1.39 (m, 3H) 1.55 (m,3H) 1.71 (s, 3H) 4.03 (q, J=6.74 Hz, 2H) 4.56 (m, 1H) 5.21 (s, 1H) 6.85(s, 1H) 7.01 (d, J=8.79 Hz, 1H) 7.13 (m, 7H) 7.46 (dd, J=9.23, 2.20 Hz,1H) 7.80 (d, J=6.59 Hz, 1H) 8.07 (m, 2H) 8.44 (s, 1H) 9.05 (s, 1H).LC-MS: 498.41 (M+H)⁺.

Example 2662-(3-Ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)-N-((R)-1-phenylethyl)acetamideTrifluoroacetic Acid Salt

A mixture of Intermediate 13 (23 mg, 0.060 mmol),(R)-α-methylbenzylamine (15.0 mg, 0.12 mmol), EDC (23 mg, 0.12 mmol),HOAT (2.5 mg, 0.01-8 mmol), and DIPEA (24 mg, 0.18 mmol) in CH₂Cl₂/DMF(2 mL, 4:1) was stirred at rt overnight. The reaction was concentratedand purified via preparative HPLC (MeOH/H₂O/TFA) to provide Example 266(28 mg, 97%) as a yellow solid. LC-MS: 484.44 (M+H)⁺.

Examples 267-274 were prepared as part of a library, from Intermediate13 and amines or amine hydrochloric acid salts that were eithercommercially available or prepared as described in the previousexamples. The following coupling procedure was used: To an individualwell of a 48-position MiniBlock® XT reactor was added 100 μL of a 0.25 Msolution of the amine in dimethylformamide (DMF) (0.025 mmol, 1.25 eq);25 μL of a 1.0 M solution of 1-hydroxybenzotriazole in DMF (0.025 mmol,1.25 eq); 100 μL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.025mmol, 1.25 eq); 100 μL of DCE; and 40 μL of a 0.50 M solution ofIntermediate 13 (0.020 mmol, 1.0 eq) in DMF and N-ethyldiisopropylamine(0.060 mmol, 3.0 eq). The reactor was agitated for 3 h at 50° C., thencooled to rt. The crude product was diluted with methanol to a totalvolume of 1 mL, then purified by standard preparative HPLC-MS(H₂O/MeOH/0.1% TFA, gradient 35-90% MeOH over 12 min, 20×100 mm 5 μm YMCODS-A column) utilizing mass-directed fractionation. The purified samplewas reconstituted in 1:1/MeOH:DCE, transferred to a tared 2.5 mL plasticmicrotube, dried via centrifugal evaporation and weighed. The finalproduct was analyzed by HPLC-MS (H₂O/MeOH/0.1% TFA).

Table 1 exemplifies these Examples with their substituents and LC-MSdata.

TABLE 1 LC-MS: Example # Name Z (M + H)⁺ 2672-(3-ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)-N-(pyridin-2-ylmethyl)acetamidetrifluoroaceticacid salt

471.090 268N-(3-Acetylamino-benzyl)-2-(3-ethoxy-4-isopropoxy-phenyl)-2-(isoquinolin-6-ylamino)-acetamidetrifluoroaceticacid salt

527.200 269N-(2-(methylsulfonyl)benzyl)-2-(3-ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)acetamidetrifluoroaceticacid salt

548.060 270N-(2-(piperidin-1-yl)benzyl)-2-(3-ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)acetamidetrifluoroaceticacid salt

553.190 2712-(3-Ethoxy-4-isopropoxy-phenyl)-2-(isoquinolin-6-ylamino)-N-(2-sulfamoyl-benzyl)-acetamidetrifluoroacetic acid salt

549.070 272N-(4-chloro-2-fluorobenzyl)-2-(3-ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)acetamidetrifluoroaceticacid salt

522.030 273N-(2-(trifluoromethylthio)benzyl)-2-(3-ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)acetamidetrifluoroaceticacid salt

570.240 274N-(4-hydroxy-3-methoxybenzyl)-2-(3-ethoxy-4-isopropoxyphenyl)-2-(isoquinolin-6-ylamino)acetamidetrifluoroacetic-acid salt

516.290

Example 275N-(5-Acetamido-2-(ethylsulfonyl)benzyl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3,5-diethoxyphenyl)acetamidetrifluoroacetic acid salt

275A 3,5-Diethoxybenzaldehyde

A mixture of 3,5-dihydroxybenzaldehyde (1.38 g, 10 mmol), ethyl iodide(2.00 mL, 25 mmol), and potassium carbonate (3.45 g, 25 mmol) inacetonitrile (10 mL) was stirred at 80° C. overnight. TLC showedstarting material and monoalkylated product, so additional ethyl iodide(0.5 mL, 6.2 mmol) was added and heating continued for 7 h. The reactionmixture was concentrated in vacuo. The residue was partitioned betweendichloro-methane and water, and the organic extract was thenconcentrated in vacuo. The residual material was purified by silica gelchromatography (gradient from 0 to 30% EtOAc in hexanes) to give 275A(1.3 g, 67%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.43(t, J=6.81 Hz, 6H) 4.07 (q, J=7.03 Hz, 4H) 6.69 (t, J=1.98 Hz, 1H) 6.99(d, J=2.64 Hz, 2H) 9.89 (s, 1H).

275B 2-(3,5-Diethoxyphenyl)-2-hydroxyacetonitrile

Sodium hydrogen sulfite (2.09 g, 20 mmol) was added to a solution ofaldehyde 275A (1.3 g, 6.7 mmol) in EtOAc (15 mL). Water (5 mL) was thenadded, followed by potassium cyanide (1.32 g, 20 mmol). The resultingclear solution was stirred at rt for 48 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The organic layerswere dried and concentrated in vacuo. The residue was purified by silicagel chromatography (gradient from 0 to 30% EtOAc in hexanes) to give275B (1.07 g, 72%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.41(t, J=7.03 Hz, 6H) 4.03 (q, J=7.03 Hz, 4H) 5.45 (d, J=7.47 Hz, 1H) 6.48(t, J=2.20 Hz, 1H) 6.64 (d, J=2.20 Hz, 2H).

275C Methyl 2-(3,5-diethoxyphenyl)-2-hydroxyacetate

A solution of cyanohydrin 275B (1.04 g, 4.84 mmol) in ether (25 mL)wascooled to 0° C. Methanol (1.03 mL, 24 mmol) was added, followed byhydrogen chloride (4 N solution in dioxane, 7 mL). The reaction mixturewas placed in a refrigerator for one week. The reaction mixture wasfiltered, to give a white solid (1.61 g). The solid (0.78 g) wasdissolved in dichloromethane (5 mL) and water (5 mL) and stirred for 1h. The aqueous layer was extracted with dichloromethane. The organicextracts were dried and concentrated to give 275C (0.73 g, 93%) as aclear oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.40 (t, J=7.03 Hz, 6H) 3.40(d, J=5.71 Hz, 1H) 3.77 (s, 3H) 4.01 (q, J=7.03 Hz, 4H) 5.08 (d, J=5.71Hz, 1H) 6.41 (t, J=2.20 Hz, 1H) 6.55 (d, J=2.20 Hz, 2H).

275D Methyl 2-(3,5-diethoxyphenyl)-2-(methylsulfonyloxy)acetate

Methanesulfonyl chloride (0.148 mL, 1.91 mmol) was added slowly dropwiseto a solution of 275C (0.35 g, 1.38 mmol) and TEA (0.288 mL, 2.07 mmol)in dichloromethane (10 mL). The reaction was stirred at rt until tlcindicated completion. It was diluted with EtOAc, and washed with coldhydrochloric acid (0.1 N), water, and then brine. The organic layerswere dried and concentrated in vacuo to give 275D (0.43 g, 94%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.41 (t, J=6.81 Hz, 6H) 3.07(s, 3H) 3.78 (s, 3H) 4.01 (q, J=7.03 Hz, 4H) 5.82 (s, 1H) 6.47 (t,J=2.20 Hz, 1H) 6.56 (d, J=2.20 Hz, 2H).

275E Methyl2-(1-di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(3,5-diethoxyphenyl)acetate

A solution of mesylate 275D (0.087 g, 0.26 mmol), Intermediate 1 (108mg, 0.300 mmol), and DIEA (0.080 mL, 0.46 mmol) in DMF was stirred at90° C. overnight. The reaction mixture was concentrated and the residuewas purified by chromatography on silica gel (gradient from 20 to 50%EtOAc in hexanes) to give 275E (32 mg, 21%). ¹H NMR (400 MHz, CDCl₃) δppm 1.31 (s, 18H) 1.39 (t, J=7.03 Hz, 6H) 3.78 (s, 3H) 4.00 (q, J=7.03Hz, 4H) 5.08 (d, J=5.27 Hz, 1H) 5.51 (d, J=5.27 Hz, 1H) 6.41 (t, J=1.98Hz, 1H) 6.53 (d, J=1.76 Hz, 1H) 6.66 (d, J=1.76 Hz, 2H) 7.02 (dd,J=9.01, 1.98 Hz, 1H) 7.29 (d, J=6.15 Hz, 1H) 7.71 (d, J=9.23 Hz, 1H)8.18 (d, J=5.71 Hz, 1H).

275F2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(3,5-diethoxyphenyl)aceticacid

Using a procedure similar to that used to prepare Intermediate 13, 275E(32 mg, 0.054 mmol) was hydrolyzed to give 275F (39 mg, 100%) as anoff-white solid. LC-MS: 582.2 (M+H)⁺.

275G

Example 275 (20 mg, 41%, white solid) was prepared from 275F (39 mg,0.067 mmol) and Intermediate 9 (22 mg, 0.085 mmol) using the generalcoupling-deprotection procedure. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t,J=7.25 Hz, 3H) 1.33 (t, J=6.81 Hz, 6H) 2.12 (s, 3H) 3.22 (q, J=7.47 Hz,2H) 3.88-4.02 (m, 4H) 4.61-4.77 (m, J=12.96, 5.93 Hz, 2H) 5.09 (s, 1H)6.40 (t, J=2.20 Hz, 1H) 6.58-6.64 (m, 3H) 6.75 (d, J=7.47 Hz, 1H) 7.16(dd, J=9.01, 1.98 Hz, 1H) 7.29 (d, J=7.47 Hz, 1H) 7.62-7.68 (m, 1H) 7.71(d, J=1.32 Hz, 1H) 7.77 (d, J=8.79 Hz, 1H) 8.04 (d, J=9.23 Hz, 1H) 8.58(t, J=6.15 Hz, 1H); LC-MS: 620.2 (M+H)⁺.

Example 276 Ethyl3-((2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluorophenyl)acetamido)methyl)-4-(ethylsulfonyl)phenylcarbamatetrifluoroacetic acid salt

276A 5-Amino-2-(ethylsulfonyl)benzonitrile

Iron powder (1.67 g, 29.9 mmol) was added portionwise over 1.5 h to asuspension of Intermediate 9B (0.95 g, 4.0 mmol) in a mixture of aceticacid (3 mL), ethanol (26 mL), and water (5 mL) at 115° C. The reactionwas cooled to rt, filtered through glass fibre filter paper, neutralizedwith saturated sodium bicarbonate, and extracted with ethyl acetate(4×). The combined organics were washed with brine, dried, andconcentrated in vacuo. The residue was purified by silica gelchromatography to give 276A (0.312 g, 38%), along with recoveredstarting material (0.737 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.31 (t,J=7.47 Hz, 3H) 3.31 (q, J=7.18 Hz, 2H) 4.47 (s, 2H) 6.89 (dd, J=8.79,2.64 Hz, 1H) 7.04 (d, J=2.64 Hz, 1H) 7.86 (d, J=8.35 Hz, 1H).

276B Ethyl 3-(aminomethyl)-4-(ethylsulfonyl)phenylcarbamate

Ethyl chloroformate (0.077 mL, 0.8 mmol) was added dropwise to asolution of 276A (84 mg, 0.4 mmol) in pyridine (0.5 mL) at 0° C. Thereaction mixture was warmed to rt, stirred for 30 min, and then storedovernight in a refrigerator. The solvent was removed in vacuo and theresidue was triturated with water. This solid was hydrogenated (55 psi)over Raney nickel in MeOH overnight. The solution was filtered andconcentrated in vacuo to give 276B (36 mg, 31%). ¹H NMR (400 MHz, CD₃OD)δ ppm 1.25 (t, J=7.47 Hz, 3H) 1.32 (t, J=7.03 Hz, 3H) 3.24-3.33 (m, 2H)4.23 (q, J=7.03 Hz, 2H) 4.33 (s, 2H) 7.72 (d, J=8.35 Hz, 1H) 7.85 (s,1H) 7.92 (d, J=8.79 Hz, 1H).

276C

Example 276 (38 mg, 52%, yellow solid) was prepared from 276B (35 mg,0.13 mmol) and 73A (56 mg, 0.1 μmol) using the generalcoupling-deprotection procedure. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.18 (t,J=7.25 Hz, 3H) 1.32 (t, J=6.81 Hz, 3H) 3.19-3.30 (m, 2H) 3.74 (s, 3H)3.79-4.02 (m, 2H) 4.58-4.81 (m, 2H) 5.46 (s, 1H) 6.66 (s, 1H) 6.78 (d,J=7.03 Hz, 1H) 6.83-6.96 (m, 2H) 7.09 (t, J=9.01 Hz, 1H) 7.18 (d, J=9.23Hz, 1H) 7.31 (d, J=7.03 Hz, 1H) 7.51 (d, J=8.79 Hz, 1H) 7.65 (s, 1H)7.75 (d, J=8.35 Hz, 1H) 8.08 (d, J=9.23 Hz, 1H) 8.73 (t, J=5.93 Hz, 1H)9.64 (s, 1H); LC-MS: 610.2 (M+H)⁺.

Example 277 Isopropyl3-((2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluorophenyl)acetamido)methyl)-4-(ethylsulfonyl)phenylcarbamatetrifluoroacetic acid salt

277A Isopropyl 3-(aminomethyl)-4-(ethylsulfonyl)phenylcarbamate

Using a procedure analogous to that used to prepare 276B, isopropylchloroformate (0.8 mL, 0.8 mmol, 1M solution in toluene) was reactedwith 276A (84 mg, 0.4 mmol) followed by hydrogenation to give 277A (20mg, 17%). LC-MS: 301.3 (M+H)⁺.

277B

Example 277 (21 mg, 55%, yellow solid) was prepared from 277A (20 mg,0.067 mmol) and 73A (28 mg, 0.050 mmol) using the generalcoupling-deprotection procedure. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (t,J=7.47 Hz, 3H) 1.27-1.36 (m, 9H) 3.25 (q, J=7.32 Hz, 2H) 3.77-3.95 (m,2H) 4.64-4.78 (m, 1H) 4.91-4.99 (m, 2H) 5.47 (s, 1H) 6.67 (d, J=2.20 Hz,1H) 6.79 (d, J=7.47 Hz, 1H) 6.84-6.92 (m, 2H) 7.08 (t, J=9.45 Hz, 1H)7.18 (dd, J=9.23, 2.20 Hz, 1H) 7.31 (d, J=7.03 Hz, 1H) 7.51 (dd, J=8.35,2.20 Hz, 1H) 7.68 (d, J=2.20 Hz, 1H) 7.74 (d, J=8.79 Hz, 1H) 8.08 (d,J=9.23 Hz, 1H) 8.67 (t, J=6.15 Hz, 1H) 9.59 (s, 1H); LC-MS: 638.2(M+H)⁺.

Example 278 Isobutyl3-((2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluorophenyl)acetamido)methyl)-4-(ethylsulfonyl)phenylcarbamatetrifluoroacetic acid salt

278A Isobutyl 3-(aminomethyl)-4-(ethylsulfonyl)phenylcarbamate

Using a procedure analogous to that used to prepare 276B, isobutylchloroformate (0.104 mL, 0.8 mmol) was reacted with 276A (84 mg, 0.4mmol) followed by hydrogenation to give 278A (80 mg, 64%). LC-MS: 315.3(M+H)⁺.

278B

Example 278 (21 mg, 55%, yellow solid) was prepared from 278A (20 mg,0.067 mmol) and 73A (28 mg, 0.050 mmol) using the generalcoupling-deprotection procedure. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.95-0.98(m, 3H) 0.99 (s, 3H) 1.17 (t, J=7.47 Hz, 3H) 1.30 (t, J=7.03 Hz, 3H)1.97 (dq, J=13.40, 6.59 Hz, 1H) 3.26 (q, J=7.18 Hz, 2H) 3.78-3.96 (m,4H) 4.64-4.79 (m, 2H) 5.43-5.50 (m, 1H) 6.67 (d, J=2.20 Hz, 1H) 6.77 (d,J=7.03 Hz, 1H) 6.82-6.95 (m, 2H) 7.08 (t, J=9.23 Hz, 1H) 7.16 (dd,J=9.01, 2.42 Hz, 1H) 7.30 (d, J=7.03 Hz, 1H) 7.52 (dd, J=8.79, 2.20 Hz,1H) 7.69 (s, 1H) 7.74 (d, J=8.79 Hz, 1H) 8.06 (d, J=9.23 Hz, 1H) 8.70(t, J=5.93 Hz, 1H) 9.65 (s, 1H); LC-MS: 638.2 (M+H)⁺.

Example 279N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluorophenyl)acetamido)methyl)-4-(ethylsulfonyl)phenyl)pentanamidetrifluoroacetic acid salt

279A N-(3-(Aminomethyl)-4-(ethylsulfonyl)phenyl)pentanamide

Using a procedure analogous to that used to prepare 276B, butyrylchloride (0.083 mL, 0.8 mmol) was reacted with 276A (84 mg, 0.4 mmol)followed by hydrogenation to give 279A (36 mg, 32%). LC-MS: 285.3(M+H)⁺.

279B

Example 279 (21 mg, 39%, yellow solid) was prepared from 279A (36 mg,0.13 mmol) and 73A (56 mg, 0.10 mmol) using the generalcoupling-deprotection procedure. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.99 (t,J=7.47 Hz, 3H) 1.17 (t, J=7.25 Hz, 3H) 1.30 (t, J=7.03 Hz, 3H) 1.71 (tq,J=7.47 Hz, 1H) 2.36 (t, J=7.47 Hz, 2H) 3.26 (q, J=7.32 Hz, 2H) 3.35 (s,1H) 3.81-3.94 (m, 2H) 4.69-4.75 (m, J=5.71 Hz, 2H) 5.47 (s, 1H) 6.67 (d,J=1.76 Hz, 1H) 6.78 (d, J=7.47 Hz, 1H) 6.85-6.93 (m, 2H) 7.08 (t, J=9.23Hz, 1H) 7.17 (dd, J=9.23, 2.20 Hz, 1H) 7.31 (d, J=7.03 Hz, 1H) 7.67 (dd,J=8.57, 1.98 Hz, 1H) 7.78 (d, J=8.10 Hz, 1H) 7.85 (d, J=2.20 Hz, 1H)8.07 (d, J=9.23 Hz, 1H) 8.68 (t, J=5.93 Hz, 1H); LC-MS: 622.2 (M+H)⁺.

Example 280(R)-3-((R)-2-(1-Aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-4-methylphenyl)acetamido)-3-(2-(isopropylsulfonyl)phenyl)propanoicacid trifluoroacetic acid salt

280A Bis(4-fluoro-2-methylphenyl) carbonate

To a solution of 4-fluoro-2-methylphenol (3.8 g, 30.2 mmol) in toluene(8.0 mL) was added pyridine (5.3 mL) and phosgene (1.9M in toluene, 8.0mL) at 0° C. The mixture was stirred for 2 h at rt before it wasquenched by water and extracted with EtOAc. The combined organic layerwas washed with brine, dried over MgSO₄ and concentrated to give a whitesolid product 280A. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.30 (s, 6H) 6.87-7.05(m, 4H) 7.15 (dd, J=8.79, 4.83 Hz, 2H).

280B Bis(4-fluoro-5-iodo-2-methylphenyl)carbonate

To 280A (2.3 g, 8.3 mmol) in trifluoroacetic acid (25 mL) was addedN-iodosuccinimide (7.4 g). The mixture was stirred at rt for a weekbefore it was poured into ice and extracted with EtOAc/hexanes (1:1).The organic layer was washed with saturated Na₂S₂O₃, NaHCO₃, brine anddried over MgSO₄. Evaporation of the solvent gave 280B (4.2 g, 95%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.27 (s, 6H) 6.99 (d,J=8.35 Hz, 2H) 7.56 (d, J=5.27 Hz, 2H).

280C 4-Fluoro-5-iodo-2-methylphenol

To 280B (4.2 g, 7.9 mmol) in methanol (20 mL) was added NaOH (0.63 g asa 50% aqueous solution) at 0° C. After TLC (10% EtOAc/hexanes) indicatedthe reaction was complete (2 h at 0° C.), the mixture was diluted withEtOAc, and washed with water and brine. The organic layer was dried overMgSO₄ and concentrated. The crude product was purified by silica gelchromatography to give 280C (3.36 g, 84% yield) as a solid. ¹H NMR (400MHz, CDCl₃) δ ppm 2.19 (s, 3H) 4.87 (s, 1H) 6.83 (d, J=8.35 Hz, 1H) 7.10(d, J=5.27 Hz, 1H).

280D 1-Ethoxy-4-fluoro-5-iodo-2-methylbenzene

To a solution of 280C (759 mg, 3 mmol) in acetone (7.0 mL) was addedK₂CO₃ (1.24 g) and iodoethane (0.73 mL). The mixture was stirred at rtovernight. After TLC(10% EtOAc/hexanes) indicated the reaction wascomplete, the mixture was diluted with diethyl ether, washed with waterand brine. The organic layer was dried over MgSO₄ and concentrated. Thecrude product was purified by silica gel column chromatography to give280D as a colorless oil (484 mg, 63% yield). ¹H NMR (400 MHz, CDCl₃) δppm 1.38-1.47 (m, 3H) 2.18 (s, 3H) 3.98 (t, J=7.03 Hz, 2H) 6.86 (d,J=7.91 Hz, 1H) 7.06 (d, J=4.83 Hz, 1H).

280E 5-Ethoxy-2-fluoro-4-methylphenylboronic acid

To 280D (240 mg, 0.85 mmol) in THF (3.0 mL) was added n-BuLi (1.6M inhexanes, 0.69 mL) at −78° C. After stirring for 10 min, trimethyl borate(0.19 mL) was introduced. The mixture was stirred from −78° C. to rt for3 h before it was quenched by 1N HCl and extracted with ethyl acetate.The organic extracts were washed with saturated Na₂S₂O₃, brine and driedover MgSO₄. Evaporation of the solvent gave product 280E (130 mg, 77%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.39 (t, J=7.03 Hz, 3H)2.19 (s, 3H) 4.00 (q, J=6.74 Hz, 2H) 6.78-6.86 (m, 2H).

280F2-(1-(bis(tert-Butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-4-methylphenyl)aceticacid

A mixture of 280E (48 mg, 0.24 mmol), Intermediate 1 (72 mg, 0.2 mmol)and glyoxylic acid monohydrate (22 mg, 0.24 mmol) in acetonitrile (0.4mL) and DMF (0.04 mL) was heated at 100° C. for 30 min in a MicrowaveReactor. The crude product was purified by silica gelchromatography(CH₂Cl₂:MeOH=100:15) to give 280F (70 mg, 61% yield) as asolid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.25-1.36 (m, 21H) 2.16-2.17(m, 3H) 3.90-4.00 (m, 2H) 5.48-5.54 (m, 1H) 6.73 (d, J=2.20 Hz, 1H) 6.96(d, J=2.64 Hz, 1H) 6.97 (s, 1H) 7.29 (dd, J=9.23, 2.20 Hz, 1H) 7.46 (d,J=5.71 Hz, 1H) 7.64 (d, J=9.23 Hz, 1H) 7.97 (s, 1H) 8.04 (d, J=5.71 Hz,1H), LC-MS 570 (M+1).

280G

Example 280 was prepared according to the general coupling-deprotectionusing 280F and 116E followed by hydrolysis of the ester. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.05-1.51 (m, 9H) 2.19 (s, 3H) 3.10-3.25 (m, 3H)3.55-3.89 (m, 2H) 5.66 (s, 1H) 5.93-6.06 (m, 1H) 6.69-6.73 (m, 2H)6.95-7.03 (m, 2H) 7.13-7.19 (m, 2H) 7.33-7.41 (m, 2H) 7.46 (t, J=7.03Hz, 1H) 7.89 (d, J=7.91 Hz, 1H) 8.11 (d, J=8.79 Hz, 1H); LC-MS 623(M+H).

Example 281(R)-3-((R)-2-(1-Aminoisoquinolin-6-ylamino)-2-(5-ethyl-2-fluoro-4-methoxyphenyl)acetamido)-3-(2-(isopropylsulfonyl)phenyl)propanoicacid trifluoroacetic acid salt

281A 5-Ethyl-2-fluorophenol

To a solution of 1-ethyl-4-fluorobenzene (7.2 g, 58 mmol) in THF (30 mL)and N,N,N′,N″,N″-pentamethyldiethylenetriamine (3.0 mL) was added n-BuLi(1.6M in hexane, 42 mL) at −78° C. After 1 h stirring, trimethyl borate(13 mL) was added. The mixture was stirred from −78° C. to rt overnight.It was quenched by acetic acid (5.0 mL) and hydrogen peroxide solution(30% in water) at 0° C. The mixture was stirred for 2 h before extractedwith EtOAc. The organic extracts were washed with brine, dried overMgSO₄ and concentrate to give 281A (7.6 g, 94% yield) as an oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.19 (t, J=7.69 Hz, 3H) 2.56 (q, J=7.62 Hz, 2H)6.60-6.71 (m, 1H) 6.83 (dd, J=8.79, 2.20 Hz, 1H) 6.95 (dd, J=10.55, 8.35Hz, 1H).

281B tert-Butyl(5-ethyl-2-fluorophenoxy)dimethylsilane

To 281A (3.75 g, 26.8 mmol) in DMF (20 mL) was addedtert-butyldimethylsilyl chloride (6.1 g) and imidazole (2.6 g). Themixture was stirred at rt for overnight. It was then diluted withEtOAc/hexanes (1:4) and washed with water and brine. The organicextracts were dried and concentrated. The crude product was purified bysilica gel column chromatography to give 281B (4.46 g, 66% yield) as anoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.21 (s, 6H) 0.99 (s, 9H) 1.18 (t,J=7.69 Hz, 3H) 2.54 (q, J=7.76 Hz, 2H) 6.64-6.76 (m, 2H) 6.93 (dd,J=10.55, 8.35 Hz, 1H).

281C 3-(tert-Butyldimethylsilyloxy)-5-ethyl-2-fluorobenzaldehyde

To 281B (625 mg, 2.46 mmol) in THF (10 mL) andN,N,N′,N″,N″-pentamethyldiethylenetriamine (0.77 mL) was added n-BuLi(1.6M in hexane, 1.77 mL) at −78° C. After stirring for 45 min at −35°C., DMF (0.94 mL) was added at −78° C. and the reaction was slowlywarmed up to rt. The mixture was stirred at rt for 1 h, diluted withEtOAc. The organic extracts were washed with saturated NaHCO₃, brine anddried. The crude product was purified by silica gel columnchromatography to give 281C (615 mg, 89% yield) as an oil. ¹H NMR (400MHz, CDCl₃) δ ppm 0.21 (s, 6H) 1.01 (s, 9H) 1.21 (t, J=7.47 Hz, 3H) 2.59(q, J=7.47 Hz, 2H) 6.99 (dd, J=7.91, 2.20 Hz, 1H) 7.21-7.27 (m, 1H)10.30 (s, 1H).

281D 5-Ethyl-2-fluoro-3-methoxybenzaldehyde

To 281C (244 mg, 0.87 mmol) in DMF (2.0 mL) was added potassium fluoride(100 mg) and iodomethane (0.13 mL). The mixture was stirred at rtovernight. It was diluted with EtOAc and the organic extracts werewashed with brine and dried. The crude product was purified by silicagel column chromatography to give 281D (158 mg, 100% yield) as an oil.¹H NMR (400 MHz, CDCl₃) (ppm 1.23 (t, J=7.47 Hz, 3H) 2.64 (q, J=7.62 Hz,2H) 3.92 (s, 3H) 7.02 (dd, J=8.13, 1.98 Hz, 1H) 7.23 (dd, J=5.27, 2.20Hz, 1H) 10.35 (s, 1H).

281E 2-(5-Ethyl-2-fluoro-3-methoxyphenyl)-2-hydroxyacetonitrile

To 281D (630 mg, 3.46 mmol) in ethyl acetate (10 mL) was added asolution of KCN (676 mg) and NaHSO₃ (1.08 g) dissolved in H₂O (10 mL).It was left stirring overnight before extracted with ethyl acetate (2×50mL). The combined organic extracts were dried and concentrated. Thecrude product was purified by silica gel column chromatography to give281E (685 mg, 92% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) (ppm 1.23(t, J=7.47 Hz, 3H) 2.64 (q, J=7.62 Hz, 2H) 3.89 (s, 3H) 5.76 (s, 1H)6.86 (dd, J=7.91, 2.20 Hz, 1H) 6.98 (dd, J=5.93, 1.98 Hz, 1H).

281F Methyl 2-(5-ethyl-2-fluoro-3-methoxyphenyl)-2-hydroxyacetate

To 281E (630 mg, 2.93 mmol) in anhydrous diethyl ether (10 mL) at 0° C.was added MeOH (1.2 mL) and 4.0 N HCl in dioxane (2.9 mL). The mixturewas stirred at 0° C. for 30 min and then at rt over night. Solvent wasremoved to give methyl2-(3-methoxy-5-ethyl-2-fluorophenyl)-2-hydroxyacetimidate HCl salt. Tothis salt in CH₂Cl₂ (5.0 mL) was added H₂O (8.0 mL). The mixture wasstirred at rt for 30 min, then extracted with CH₂Cl₂ (2×50 mL). Thecombined organic extracts were dried and concentrated. The crude waspurified by silica gel column chromatography to give 281F (632 mg, 89%yield) as a viscous oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.21 (t, J=7.69Hz, 3H) 2.59 (q, J=7.47 Hz, 2H) 3.76 (s, 3H) 3.87 (s, 3H) 5.38 (s, 1H)6.65-6.85 (m, 2H).

281G Methyl2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(5-ethyl-2-fluoro-3-methoxyphenyl)acetate

To 281F (257 mg, 1.06 mmol) in CH₂Cl₂ (5.0 mL) at 0° C. was addedtrifluoromethanesulfonic anhydride (0.2 mL) and 2,6-lutidine (0.19 mL).The mixture was stirred for 15 min before Intermediate 1 (343 mg, 0.57mmol) and 2,6-lutidine (0.37 mL) in CH₂Cl₂ (2.0 mL) was added. Thereaction was left stirring from 0° C. to rt for 3.0 h. It was dilutedwith ethyl acetate, washed with 0.5 N HCl (3×20 mL). The organic extractwas dried and concentrated. A silica gel column chromatographypurification gave product 281G (520 mg, 84% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.17 (t, J=7.47 Hz, 3H) 1.27 (s, 18H) 2.58 (q, J=7.62 Hz,2H) 3.76 (s, 3H) 3.87 (s, 3H) 5.62 (s, 1H) 6.72 (d, J=2.20 Hz, 1H)6.85-6.93 (m, 2H) 7.07 (d, J=7.91 Hz, 1H) 7.28 (dd, J=9.23, 2.64 Hz, 1H)7.46 (d, J=5.71 Hz, 1H) 7.64 (d, J=8.79 Hz, 1H) 8.05 (d, J=5.71 Hz, 1H).LC-MS 584 (M+H).

281H2-(1-(bis(tert-Butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(5-ethyl-2-fluoro-3-methoxyphenyl)aceticacid

281G (77 mg, 0.13 mmol) was hydrolyzed with NaOH (1.0 N, 0.19 mL, 0.19mmol) in THF (0.6 mL) and MeOH (0.3 mL) at rt for 2 h. Afteracidification with 5% KHSO₄, it was extracted with ethyl acetate (2×30mL). The organic extract was dried and concentrated to give a solidproduct 281H (64 mg, 84% yield). LC-MS 570 (M+H)⁺.

281I

Example 281 was prepared according to the general coupling-deprotectionusing 281H and 116E followed by hydrolysis of the ester. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.05-1.11 (m, 6H) 1.44 (d, J=6.59 Hz, 3H)2.46-2.57 (m, 2H) 2.69-2.91 (m, 2H) 3.89 (s, 3H) 4.16-4.32 (m, 1H) 5.42(s, 1H) 5.95-6.06 (m, 1H) 6.66-6.74 (m, 2H) 6.93-7.00 (m, 2H) 7.17 (d,J=7.91 Hz, 2H) 7.32-7.40 (m, 2H) 7.45 (t, J=7.69 Hz, 1H) 7.89 (d, J=7.47Hz, 1H) 8.10 (d, J=9.23 Hz, 1H); LC-MS 623 (M+H).

Example 282(R)-3-((R)-2-(1-Aminoisoquinolin-6-ylamino)-2-(5-chloro-2-fluorophenyl)acetamido)-3-(2-(isopropylsulfonyl)-5-(methoxycarbonylamino)phenyl)propanoicacid trifluoroacetic acid salt

282A 2-(2-Fluoro-5-chlorophenyl)-2-hydroxyacetonitrile

To 2-fluoro-5-chloro-benzaldehyde (12.7 g, 17 mmol) in ethyl acetate (50mL) was added a solution of KCN (3.3 g) and NaHSO₃ (5.3 g) dissolved inH₂O (25 mL). It was left stirring overnight before extracted with ethylacetate (3×50 mL). The combined organic extracts were dried andconcentrated. The crude product was purified by silica gel columnchromatography to give 282A (3.1 g, 99% yield) as an oil.

282B Methyl 2-(5-chloro-2-fluorophenyl)-2-hydroxyacetate

To 282A (640 mg, 3.48 mmol) in anhydrous diethyl ether (15 mL) at 0° C.was added MeOH (1.4 mL) and 4.0 N HCl in dioxane (3.5 mL). The mixturewas stirred at 0° C. for 30 min and then at rt for 4 h. The solvent wasremoved to give methyl 2-(5-chloro-2-fluorophenyl)-2-hydroxyacetimidateHCl salt. To this salt in CH₂Cl₂ (10 mL) was added H₂O (10 mL). Themixture was stirred at rt for 30 min, then extracted with CH₂Cl₂ (2×50mL). The combined organic extracts were dried and concentrated. Thecrude product was purified by silica gel column chromatography to give282B (610 mg, 80% yield) as a viscous oil. ¹H NMR (400 MHz, CDCl₃) δ ppm3.55 (d, J=4.83 Hz, 1H) 3.80 (s, 3H) 5.38 (d, J=4.83 Hz, 1H) 7.03 (t,J=9.23 Hz, 1H) 7.27-7.31 (m, 1H) 7.39 (dd, J=6.15, 2.64 Hz, 1H).

282C Methyl2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(5-chloro-2-fluorophenyl)acetate

To 282B (320 mg, 1.47 mmol) in CH₂Cl₂ (5.0 mL) at 0° C. was addedtrifluoromethanesulfonic anhydride (0.27 mL) and 2,6-lutidine (0.26 mL).The mixture was stirred for 15 min before Intermediate 1 (475 mg, 1.32mmol) and 2,6-lutidine (0.51 mL) in CH₂Cl₂ (2.0 mL) were added. Thereaction was left stirring from 0° C. to rt for 3.0 h. It was dilutedwith ethyl acetate, washed with 0.5 N HCl (3×20 mL). The organic extractwas dried and concentrated. A silica gel column chromatographypurification gave product 282C (447 mg, 60% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.16 (s, 18H) 3.67 (s, 3H) 5.58 (s, 1H) 6.63 (d, J=2.20 Hz,1 H) 7.10 (t, J=9.23 Hz, 1H) 7.19 (dd, J=9.01, 2.42 Hz, 1H) 7.22-7.30(m, 1H) 7.37 (d, J=5.71 Hz, 1H) 7.44 (d, J=2.64 Hz, 1H) 7.56 (d, J=9.23Hz, 1H) 7.95 (d, J=5.71 Hz, 1H); LC-MS 560 (M+H).

282D2-(1-(bis(tert-Butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(5-chloro-2-fluorophenyl)aceticacid

282C (440 mg, 0.79 mmol) was hydrolyzed with NaOH (1.0 N, 0.95 mL, 0.95mmol) in THF (4 mL) and MeOH (0.5 mL) at rt for 2 h. After acidificationwith 5% KHSO₄, it was extracted with ethyl acetate (2×30 mL). Theorganic extract was dried and concentrated to give a solid product 282D(400 mg, 93% yield). ¹H NMR (400 MHz, Methanol-d₄) δ ppm 1.29 (s, 18H)5.62 (s, 1H) 6.77 (d, J=1.76 Hz, 1H) 7.22 (t, J=9.23 Hz, 1H) 7.33-7.40(m, 2H) 7.54-7.59 (m, 2H) 7.73 (d, J=9.23 Hz, 1H) 8.07 (d, J=6.15 Hz,1H); LC-MS 546 (M+H)⁺.

282E (R)-Methyl3-(tert-butoxycarbonylamino)-3-(2-(isopropylsulfonyl)-5-(methoxycarbonylamino)phenyl)propanoate

To 98E (1.5 g, 3.4 mmol) in EtOH (15 mL) at rt was added Oxone® (4.2 g,6.8 mmol) in H₂O (40 mL). The mixture was stirred at rt over night. EtOHwas removed in vaccuo. The residue was suspended in EtOAc and washedwith water, Na₂S₂O₃ and brine. The organic layer was dried over Na₂SO₄.After evaporation of solvent, the crude was purified by silica gelcolumn chromatography eluting with gradient EtOAc in hexanes to give282E as a white solid (1.5 g, 93% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm1.14 (d, J=7.03 Hz, 3H) 1.18 (d, J=7.05 Hz, 3H) 1.36 (s, 9H) 1.47 (d,J=6.59 Hz, 3H) 2.83-2.90 (m, 1H) 2.93-3.00 (m, 1H) 3.81 (s, 3H) 3.86 (s,1H) 4.11 (m, 2H) 5.57-5.65 (m, 1H) 6.18 (s, 1H) 6.96 (s, 1H) 7.51 (d,J=2.20 Hz, 1H) 7.62 (d, J=7.91 Hz, 1H) 7.90 (d, J=8.79 Hz, 1H); LC-MS473 (M+H).

282F (R)-Methyl3-amino-3-(2-(isopropylsulfonyl)-5-(methoxycarbonylamino)phenyl)propanoatehydrochloride

To 282E (1.35 g, 2.86 mmol) in EtOAc (10 mL) was added 4.0 N HCl indioxane (15 mL, 60 mmol). The mixture was stirred at rt for 3.0 h.Solvent was removed in vaccuo to give 282F as a white solid (1.1 g, 99%yield). ¹H NMR (500 MHz, Methanol-d₄) δ ppm 1.11-1.15 (m, 6H) 1.31 (d,J=7.15 Hz, 3H) 3.04-3.11 (m, 1H) 3.15-3.20 (m, 1H) 3.50 (ddd, J=13.61,6.74, 6.60 Hz, 1H) 3.70 (s, 3H) 4.05 (q, J=7.15 Hz, 2H) 5.44 (t, J=7.42Hz, 1H) 7.51 (d, J=10.45 Hz, 1H) 7.85 (d, J=8.80 Hz, 1H) 7.99 (s, 1H),LC-MS 373 (M+H).

282G

Example 282 was prepared according to the general coupling-deprotectionusing 282D and 282F followed by hydrolysis of the ester. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.13 (d, J=6.59 Hz, 3H) 1.43 (d, J=6.59 Hz, 3H)2.71-2.93 (m, 2H) 3.66 (s, 3H) 4.13-4.30 (m, 1H) 5.39 (s, 1H) 5.85-6.00(m, 1H) 6.64 (d, J=2.20 Hz, 1H) 6.88 (d, J=7.03 Hz, 1H) 7.16 (dd,J=9.23, 2.20 Hz, 1H) 7.18-7.28 (m, 2H) 7.30-7.35 (m, 2H) 7.37-7.44 (m,1H) 7.54 (d, J=1.76 Hz, 1H) 7.76 (d, J=8.79 Hz, 1H) 8.11 (d, J=8.79 Hz,1H); LC-MS 786 (M+H).

Example 283(R)-3-((R)-2-(1-Aminoisoquinolin-6-ylamino)-2-(3-(difluoromethoxy)phenyl)acetamido)-3-(2-(isopropylsulfonyl)-5-(methoxycarbonylamino)phenyl)propanoicacid trifluoroacetic acid salt

283A 2-(3-Difluoromethoxyphenyl)-2-hydroxyacetonitrile

To 3-difluoromethoxybenzaldehyde (1.77 g, 10 mmol) in ethyl acetate (25mL) was added a solution of KCN (2.0 g) and NaHSO₃ (3.2 g) dissolved inH₂O (25 mL). It was left stirring overnight before it was extracted withethyl acetate (2×50 mL). The combined organic extracts were dried andconcentrated. The crude product was purified by silica gel columnchromatography to give 283A (1.85 g, 92% yield) as an oil. ¹H NMR (400MHz, CDCl₃) δ ppm 5.66 (s, 1H) 6.86 (t, J=73.82 Hz, 1H) 7.18 (dd,J=7.91, 2.20 Hz, 1H) 7.31 (s, 1H) 7.36-7.42 (m, 1H) 7.47 (t, J=7.91 Hz,1H).

283B Methyl 2-(3-difluoromethoxyphenyl)-2-hydroxyacetate

To 283A (1.83 g, 9.2 mmol) in anhydrous CH₂Cl₂ (30 mL) at 0 (C was addedMeOH (2.24 mL) and 4.0 N HCl in dioxane (9.2 mL). The mixture wasstirred at 0 (C for 30 min and then at rt for 4.0 h. Solvent was removedto give methyl 2-(3-(difluoromethoxy)-phenyl)-2-hydroxyacetimidate HClsalt. To this salt in CH₂Cl₂ (10 mL) was added H₂O (10 mL). The mixturewas stirred at rt for 30 min, then extracted with CH₂Cl₂ (2×50 mL). Thecombined organic extracts were dried and concentrated. The crude productwas purified by silica gel column chromatography to give 283B (700 mg,33% yield) as a viscous oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.70 (s, 3H)5.22 (s, 1H) 6.82 (t, J=74.04 Hz, 1H) 7.09 (dd, J=7.91, 2.20 Hz, 1H)7.23 (s, 1H) 7.28-7.34 (m, 1H) 7.38 (t, J=7.91 Hz, 1H).

283C Methyl2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(3-(difluoromethoxy)phenyl)acetate

To 283B (650 mg, 2.8 mmol) in CH₂Cl₂ (10 mL) at 0° C. was addedtrifluoromethanesulfonic anhydride (0.52 mL) and 2,6-lutidine (0.49 mL).The mixture was stirred for 15 min before Intermediate 1 (1.0 g, 2.8mmol) and 2,6-lutidine (0.97 mL) in CH₂Cl₂ (5.0 mL) were added. Thereaction was left stirring from 0° C. to rt for 3.0 h. It was dilutedwith ethyl acetate, and washed with 0.5 N HCl (3×20 mL). The organicextract was dried and concentrated. A silica gel column chromatographypurification gave 283C (680 mg, 42% yield). ¹H NMR (400 MHz, CDCl₃) δppm 1.27 (s, 18H) 3.76 (s, 3H) 5.44 (s, 1H) 6.56-7.03 (m, 2H) 7.10-7.14(m, 1H) 7.31 (dd, J=9.23, 2.20 Hz, 1H) 7.35 (s, 1H) 7.41-7.47 (m, 3H)7.65 (d, J=9.23 Hz, 1H) 8.04 (d, J=6.15 Hz, 1H); LC-MS 574 (M+H).

283D2-(1-(bis(tert-Butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(3-(difluoromethoxy)phenyl)aceticacid

283C (680 mg, 1.2 mmol) was hydrolyzed with NaOH (1.0 N, 1.42 mL, 1.42mmol) in THF (6 mL) and MeOH (0.5 mL) at rt for 3 h. After acidificationwith 5% KHSO₄, it was extracted with ethyl acetate (2×30 mL). Theorganic extract was dried and concentrated to give a solid product 283D(650 mg, 96% yield). ¹H NMR (400 MHz, Methanol-d₄) (ppm 1.26 (s, 18H)4.99 (s, 1H) 6.58 (d, J=2.20 Hz, 1H) 6.79 (t, J=74.26 Hz, 1H) 7.01 (dd,J=8.13, 2.42 Hz, 1H) 7.25 (dd, J=8.79, 2.20 Hz, 1H) 7.31-7.40 (m, 3H)7.47 (d, J=7.91 Hz, 1H) 7.61 (d, J=9.23 Hz, 1H) 7.99 (d, J=5.71 Hz, 1H).LC-MS 560 (M+H).

283E

Example 283 was prepared according to the general coupling-deprotectionusing 282F and 283D followed by hydrolysis of the ester. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.10 (d, J=6.59 Hz, 3H) 1.42 (d, J=6.59 Hz, 3H)2.67-2.93 (m, 2H) 3.69 (s, 3H) 4.12-4.31 (m, 1H) 5.09 (s, 1H) 5.83-5.98(m, 1H) 6.58 (s, 1H) 6.63-7.02 (m, 2H) 7.10-7.15 (m, 1H) 7.15-7.23 (m,2H) 7.28 (s, 1H) 7.31 (d, J=7.03 Hz, 1H) 7.35-7.43 (m, 2H) 7.45 (d,J=1.76 Hz, 1H) 7.72 (d, J=8.79 Hz, 1H) 8.09 (d, J=9.23 Hz, 1H); LC-MS686 (M+H).

Example 284(R)-3-((R)-2-(1-Aminoisoquinolin-6-ylamino)-2-(3-chlorophenyl)acetamido)-3-(2-(isopropylsulfonyl)-5-(methoxycarbonylamino)phenyl)propanoicacid

284A2-(1-(bis(tert-Butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(3-chlorophenyl)aceticacid

284A was prepared in procedures similar to that of 282D following steps282A to 282D starting from 3-chlorobenzaldehyde. ¹H NMR (400 MHz,Methanol-d₄) δ ppm 1.27 (s, 18H) 5.29 (s, 1H) 6.67 (d, J=1.76 Hz, 1H)7.27-7.40 (m, 3H) 7.44 (d, J=6.15 Hz, 1H) 7.53 (d, J=7.47 Hz, 1H) 7.61(s, 1H) 7.65 (d, J=9.23 Hz, 1H) 8.03 (d, J=5.71 Hz, 1H); LC-MS 530 (M+1)

284B

Example 284 was prepared according to the general coupling-deprotectionusing 282F and 284A followed by hydrolysis of the ester. ¹H NMR (400MHz, Methanol-d₄) δ ppm 0.98 (d, J=6.59 Hz, 3H) 1.30 (d, J=7.03 Hz, 3H)2.58-2.80 (m, 2H) 3.58 (s, 3H)-4.03-4.15 (m, 1H) 4.99 (s, 1H) 5.75-5.83(m, 1H) 6.47 (s, 1H) 6.71 (d, J=7.03 Hz, 1H) 7.04 (dd, J=9.23, 2.20 Hz,1H) 7.10 (dd, J=8.79, 2.20 Hz, 1H) 7.19 (d, J=7.03 Hz, 1H) 7.21-7.25 (m,2H) 7.31-7.38 (m, 3H) 7.61 (d, J=8.35 Hz, 1H) 7.96 (d, J=9.23 Hz, 1H);LC-MS 654 (M+H).

Example 285 Methyl3-((2-(3-carbamoylphenylamino)-2-(3,4-dimethoxyphenyl)acetamido)methyl)-4-(isopropylsulfonyl)phenylcarbamate

285A 2-(3-Carbamoylphenylamino)-2-(3,4-dimethoxyphenyl)acetic acid

A mixture of 3-aminobenzamide (204 mg, 1.5 mmol),3,4-dimethoxyphenylboronic acid (273 mg, 1.5 mmol) and glyoxylic acidmonohydrate (138 mg, 1.5 mmol) in acetonitrile (8.0 mL) and DMF (0.8 mL)was heated at 55° C. for 4.0 h and then stirred at rt for 18 h. Theprecipitate formed was collected by filtration and washed with ethylacetate to give 285A (390 mg, 78% yield) after drying. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.03-7.19 (m, 5H) 6.91 (d, J=9.0 Hz, 1H) 6.81 (d, J=8.00Hz, 1H) 5.05 (s, 1H) 3.83 (s, 3H) 3.72 (s, 3H). LC-MS 331 (M+H).

285B 5-Amino-2-(isopropylsulfonyl)benzonitrile

2-(Isopropylsulfonyl)-5-nitrobenzonitrile (127 mg, prepared in aprocedure similar to that of Intermediate 9B in place of ethanethiolwith 2-thiopropane) was hydrogenated with 10% Pd/C in MeOH under 60 psiover night. Pd/C was removed by filtration. The filtrate wasconcentrated to give 285B (114 mg). ¹H NMR (400 MHz, Methanol-d₄) δ ppm1.27 (d, J=6.59 Hz, 6H) 3.40 (dt, J=13.62, 6.81 Hz, 1H) 6.90 (dd,J=8.79, 2.64 Hz, 1H) 7.07 (d, J=2.20 Hz, 1H) 7.67 (d, J=8.79 Hz, 1H).

285C Methyl 3-cyano-4-(isopropylsulfonyl)phenylcarbamate

To 285B (63 mg, 0.28 mmol) in pyridine (2.0 mL) at 0° C. was addedmethyl chloroformate (0.1 mL, 1.4 mmol). The mixture was stirred at rtfor 1.0 h before it was quenched with 1.0 N HCl and extracted withEtOAc. The organic extract was dried and concentrated. A silica gelcolumn chromatography purification gave 285C (79 mg, 100% yield). ¹H NMR(400 MHz, Methanol-d₄) ppm 1.31 (d, J=6.59 Hz, 6H) 3.42-3.52 (m, 1H)7.80 (dd, J=8.79, 2.20 Hz, 1H) 7.92-7.99 (m, 2H) 8.10 (d, J=2.20 Hz,1H).

285D Methyl 3-(aminomethyl)-4-(isopropylsulfonyl)phenylcarbamate

285C (77 mg) in THF (5.0 mL) was hydrogenated with Raney-Ni under 50 psiover night. Raney-Ni was removed by filtration. The filtrate wasconcentrated to give 285D as a white solid (45 mg, 80% yield). ¹H NMR(400 MHz, Methanol-d₄) ppm 1.24 (d, J=6.59 Hz, 6H) 3.32-3.41 (m, 1H)3.76 (s, 3H) 4.03 (s, 2H) 7.61-7.68 (m, 2H) 7.81 (d, J=8.79 Hz, 1H).

285E

Example 285 was prepared according to the general coupling-deprotectionusing 285A and 285D. ¹H NMR (400 MHz, Methanol-d₄) ppm 1.07-1.13 (m, 6H)3.66 (s, 3H) 3.67 (s, 3H) 3.71 (s, 3H) 4.59 (d, J=5.71 Hz, 2H) 4.83 (s,1H) 6.76 (ddd, J=6.04, 2.97, 2.86 Hz, 1H) 6.81 (d, J=8.79 Hz, 1H)6.91-6.96 (m, 2 H) 7.07-7.14 (m, 3H) 7.44-7.50 (m, 2H) 7.67 (d, J=9.67Hz, 1H) 8.59 (t, J=6.15 Hz, 1H) 9.48 (s, 1H), LC-MS 599 (M+H).

Example 286(R)-3-((R)-2-(3-Carbamoylphenylamino)-2-(3,4-dimethoxyphenyl)acetamido)-3-(2-(isopropylsulfonyl)-5-(methoxycarbonylamino)phenyl)propanoicacid

Example 286 was prepared according to the general coupling-deprotectionusing 285A and 282F followed by hydrolysis of the ester. ¹H NMR (400MHz, Methanol-d₄) δ ppm 1.11 (d, J=6.59 Hz, 3H) 1.43 (d, J=7.03 Hz, 3H)2.67-2.83 (m, 2H) 3.73 (s, 3H) 3.78 (s, 3H) 3.81 (s, 3H) 4.16-4.31 (m,1H) 4.84 (s, 1H) 5.86-5.97 (m, 1H) 6.73 (d, J=7.91 Hz, 1H) 6.87-6.90 (m,1H) 6.95-7.03 (m, 2H) 7.09-7.21 (m, 3H) 7.29 (dd, J=8.79, 2.20 Hz, 1H)7.33 (s, 1H) 7.73 (d, J=8.35 Hz, 1H); LC-MS 657 (M+H).

Example 2872-(1-Aminoisoquinolin-6-ylamino)-N-(3-(3,3-dimethylureido)benzyl)-2-(3-ethoxyphenyl)acetamidetrifluoroacetic acid salt

287A 3-(3-Cyanophenyl)-1,1-dimethylurea

To 3-cyanophenyl isocanate (720 mg, 5 mmol) in 5 mL CH₂Cl₂, was addedEt₃N (1 g, 10 mmol) and dimethylamine hydrochloride (490 mg, 6 mmol) atrt. The mixture was stirred overnight. CH₂Cl₂ (20 mL) was added, washedwith brine (20 ml), and dried (Na₂SO₄). Purified by ISCO (0-60%EtOAc/Hex) to provide 287A (855 mg) as a light yellow solid. ¹H NMR (400MHz, CD₃OD) δ ppm 3.01 (s, 6H) 6.84 (s, 1H) 7.19-7.28 (m, 1H) 7.31 (t,J=7.91 Hz, 1H) 7.61 (d, J=8.35 Hz, 1H) 7.75 (s, 1H); LC-MS 190.20 (M+H).

287B 3-(3-(Aminomethyl)phenyl)-1,1-dimethylurea

To 287A (95 mg, 0.5 mmol) in MeOH (10 mL) was added 10% Pd/C (ca. 50mg), and the whole was hydrogenated at 60 psi for 6 h. The reaction wasfiltered and concentrated and dried to provide 287B (93 mg) as a whitesolid. LC-MS 194.48 (M+H).

287C

Example 287 was prepared according to the general coupling-deprotectionusing Intermediate 16 and 287B. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.34 (t,J=7.03 Hz, 3H) 2.98 (s, 6H) 3.98 (q, J=7.03 Hz, 2H) 4.29-4.41 (m, 2H)5.12 (s, 1H) 6.63 (s, 1H) 6.75 (d, J=7.03 Hz, 1H) 6.82 (d, J=7.47 Hz,1H) 6.84-6.91 (m, 1H) 7.08-7.17 (m, 4H) 7.18-7.23 (m, 2H) 7.24-7.31 (m,2H) 8.04 (d, J=8.79 Hz, 1H). LC-MS 513.5 (M+H).

Example 2882-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxyphenyl)-N-(3-(3-ethyl-3-methylureido)benzyl)acetamidetrifluoroacetic acid salt

288A 3-(3-Cyanophenyl)-1-ethyl-1-methylurea

288A was prepared from 3-cyanophenyl isocanate in 90% yield following aprocedure analogous to that used in the preparation of 287A. ¹H NMR (400MHz, CDCl₃) δ ppm 1.17 (t, J=7.25 Hz, 3H) 2.99 (s, 3H) 3.40 (q, J=7.32Hz, 2H) 6.83 (s, 1H) 7.25 (t, J=7.25 Hz, 1H) 7.32 (t, J=7.91 Hz, 1H)7.61 (d, J=8.35 Hz, 1H) 7.78 (s, 1H). LC-MS 204.43 (M+H).

288B 3-(3-(Aminomethyl)phenyl)-1-ethyl-1-methylurea

To 288A (273 mg, 1.35 mmol) in 15 mL THF, was added Raney-Ni (ca 50 mg),and the whole was hydrogenated at 60 psi for 5 h. The reaction wasfiltered and concentrated and purified by prep HPLC to provide 288B (158mg) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J=7.25 Hz,3H) 3.00 (s, 3H) 3.42 (q, J=7.18 Hz, 2H) 4.03 (s, 2H) 7.10 (d, J=7.03Hz, 1H) 7.26-7.43 (m, 2H) 7.49 (s, 1H). LC-MS 208.44 (M+H).

288C Example 288

Example 288 was prepared according to the general coupling-deprotectionusing Intermediate 16 and 288B. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.14 (t,J=7.25 Hz, 3H) 1.34 (t, J=7.03 Hz, 3H) 2.97 (s, 3H) 3.39 (q, J=7.18 Hz,2H) 3.97-4.07 (m, 2H) 4.28-4.43 (m, 2H) 5.12 (s, 1H) 6.64 (d, J=2.20 Hz,1H) 6.76 (d, J=7.03 Hz, 1H) 6.82 (d, J=7.91 Hz, 1H) 6.88 (dd, J=7.91,2.20 Hz, 1H) 7.07-7.13 (m, 3H) 7.15 (dd, J=9.23, 2.20 Hz, 1H) 7.19-7.25(m, 2H) 7.25-7.31 (m, 2H) 8.04 (d, J=9.23 Hz, 1H). LC-MS 527.45 (M+H).

Example 289N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxyphenyl)acetamido)methyl)phenyl)pyrrolidine-1-carboxamidetrifluoroacetic acid salt

289A N-(3-Cyanophenyl)pyrrolidine-1-carboxamide

289A was prepared from 3-cyanophenyl isocanate in 63% yield following aprocedure analogous to that used in the preparation of 287A. ¹H NMR (400MHz, CDCl₃) δ ppm 1.91-2.10 (m, 4H) 3.46 (t, J=6.81 Hz, 4H) 6.30 (s, 1H)6.30 (s, 1H) 7.24-7.30 (m, 1H) 7.35 (t, J=8.13 Hz, 1H) 7.64 (d, J=8.35Hz, 1H) 7.79 (s, 1H). LC-MS 216.35 (M+H).

289B N-(3-(Aminomethyl)phenyl)pyrrolidine-1-carboxamide

289B was prepared from 289A in 90% yield following a procedure analogousto that used in the preparation of 288B. ¹H NMR (400 MHz, CD₃OD) δ ppm1.95 (t, J=6.59 Hz, 4H) 3.45 (t, J=6.81 Hz, 4H) 4.04 (s, 2H) 7.09 (d,J=7.47 Hz, 1H) 7.32 (t, J=7.91 Hz, 1H) 7.36-7.42 (m, 1H) 7.55 (s, 1H).LC-MS 220.45 (M+H).

289C

Example 289 was prepared according to the general coupling-deprotectionusing Intermediate 16 and 289B. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.35 (t,J=7.03 Hz, 3H) 1.89-2.03 (m, 4H) 3.41 (t, J=6.59 Hz, 4H) 3.98-4.06 (m,2H) 4.28-4.45 (m, 2H) 5.11 (s, 1H) 6.64 (d, J=2.20 Hz, 1H) 6.76 (d,J=7.03 Hz, 1 H) 6.82 (d, J=7.47 Hz, 1H) 6.88 (dd, J=8.35, 1.76 Hz, 1H)7.06-7.14 (m, 3H) 7.16 (dd, J=9.23, 2.20 Hz, 1H) 7.23-7.33 (m, 4H) 8.05(d, J=9.23 Hz, 1H). LC-MS 539.46 (M+H).

Example 2902-(1-Aminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)-N-(5-(3,3-dimethylureido)-2-(isopropylsulfonyl)benzyl)acetamidetrifluoroacetic acid salt

290A 5-Amino-2-(isopropylsulfonyl)benzonitrile

Using the procedures analogous to those described for preparation ofIntermediate 9A, Intermediate 9B, and 276A, 2-fluoro-5-nitrobenzonitrileand isopropanethiol were converted to 290A.

290B 3-(3-Cyano-4-(isopropylsulfonyl)phenyl)-1,1-dimethylurea

290A (25 mg, 0.11 mmol) was dissolved in 2 mL pyridine. Dimethylcarbamyl chloride (0.025 ml, 0.3 mmol) was added at rt, and the solutionwas stirred at rt overnight. Concentrated and purified by ISCO (0-80%EtOAc/Hex) to provide

290B (12.8 mg) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.26 (d,J=7.03 Hz, 6H) 3.01 (s, 6H) 3.33-3.54 (m, 1H) 7.30 (s, 1H) 7.67-7.80 (m,1H) 7.80-7.91 (m, 1H) 8.00 (d, J=2.20 Hz, 1H). LC-MS 296.37 (M+H).

290C 3-(3-(Aminomethyl)-4-(isopropylsulfonyl)phenyl)-1,1-dimethylurea

To 290B (13 mg, 0.044 mmol) in 2 mL THF was added Raney-Ni (ca 5 mg),and the whole was hydrogenated at 60 psi for 4 h. The reaction wasfiltered and concentrated to provide 290C (13 mg, 100%) as a colorlesssolid. LC-MS 300.38 (M+H).

290D

Example 290 was prepared according to the general coupling-deprotectionusing Intermediate 15 and 290C. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (d,J=6.59 Hz, 3H) 1.21 (d, J=7.03 Hz, 3H) 1.37 (q, J=7.32 Hz, 3H) 3.02 (s,6H) 3.33-3.47 (m, 1H) 3.93-4.11 (m, 2H) 4.56-4.81 (m, 2H) 5.18 (s, 1H)6.63 (d, J=2.20 Hz, 1H) 6.79 (d, J=7.47 Hz, 1H) 7.08 (dd, J=8.13, 1.98Hz, 1H) 7.11-7.20 (m, 2H) 7.30 (d, J=7.03 Hz, 1H) 7.35 (d, J=7.91 Hz,1H) 7.49 (dd, J=8.35, 2.20 Hz, 1H) 7.57 (d, J=2.20 Hz, 1H) 7.69 (d,J=8.79 Hz, 1H) 8.00 (d, J=9.23 Hz, 1H). LC-MS 653.48 (M+H).

Example 291N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)acetamido)methyl)-4-(isopropylsulfonyl)phenyl)pyrrolidine-1-carboxamidetrifluoroacetic acid salt

291A N-(3-Cyano-4-(isopropylsulfonyl)phenyl)pyrrolidine-1-carboxamide

290A (35 mg, 0156 mmol) was dissolved in 2 mL CH₂Cl₂. NaHCO₃ (126 mg,1.5 mmol) was added, followed by phosgene (0.2 ml, 0.38 mmol) at 0° C.Stirred at rt for 2 h, filtered and concentrated, dried. The residue wasdissolved in 2 mL CH₂Cl₂, Et₃N (65 mg, 0.64 mmol) was added, followed bypyrrolidine (22 mg, 0.3 mmol) at 0° C., stirred rt for 2 h, purified byISCO (0-80% EtOAc/Hex) to provide

291A (40 mg) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.29 (d,J=6.59 Hz, 6H) 1.95 (s, 4H) 3.39-3.53 (m, 5H) 7.28 (s, 1H) 7.85 (s, 2H)8.13 (s, 1H). LC-MS 322.34 (M+H).

291BN-(3-(Aminomethyl)-4-(isopropylsulfonyl)phenyl)pyrrolidine-1-carboxamide

291B was prepared from 291A in 94% yield following a procedure analogousto that used in the preparation of 290C. ¹H NMR (400 MHz, CDCl₃) δ ppm1.20 (d, J=6.59 Hz, 6H) 1.93 (m, 4H) 3.29-3.37 (m, 1H) 3.39-3.49 (m, 4H)3.94 (s, 2H) 7.56-7.62 (m, 1H) 7.64 (d, J=2.20 Hz, 1H) 7.73 (d, J=8.79Hz, 1H). LC-MS 326.37 (M+H).

291C

Example 291 was prepared according to the general coupling-deprotectionusing Intermediate 15 and 291B. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.09 (d,J=7.03 Hz, 3H) 1.13 (d, J=6.59 Hz, 3H) 1.29 (t, J=7.03 Hz, 3H) 1.90 (s,4H) 3.26-3.33 (m, 1H) 3.36 (t, J=6.81 Hz, 4H) 3.82-4.05 (m, 2H)4.48-4.73 (m, 2H) 5.08 (s, 1H) 6.54 (d, J=1.76 Hz, 1H) 6.70 (d, J=7.03Hz, 1H) 6.98 (dd, J=8.13, 1.98 Hz, 1H) 7.02-7.11 (m, 2H) 7.21 (d, J=7.03Hz, 1H) 7.26 (d, J=8.35 Hz, 1H) 7.47 (d, J=9.23 Hz, 1H) 7.52 (t, J=2.42Hz, 1H) 7.61 (d, J=8.79 Hz, 1H) 7.97 (d, J=9.23 Hz, 1H). LC-MS 679.38(M+H).

Example 292N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)acetamido)methyl)phenyl)pyrrolidine-1-carboxamidetrifluoroacetic acid salt

Example 292 was prepared according to the general coupling-deprotectionusing Intermediate 15 and 289B. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37 (t,J=7.03 Hz, 3H) 1.88-2.03 (m, 4H) 3.36-3.46 (m, 4H) 4.03 (q, J=7.03 Hz,2H) 4.31-4.45 (m, 2H) 5.13 (s, 1H) 6.65 (d, J=2.20 Hz, 1H) 6.78 (d,J=7.03 Hz, 1H) 6.83 (d, J=7.47 Hz, 1H) 7.09 (dd, J=8.13, 1.98 Hz, 1H)7.11-7.14 (m, 1H) 7.16 (dd, J=9.23, 2.20 Hz, 1H) 7.19 (d, J=1.76 Hz, 1H)7.24-7.27 (m, 2H) 7.29 (d, J=7.03 Hz, 1H) 7.33-7.37 (m, 1H) 8.06 (d,J=9.23 Hz, 1H). LC-MS 573.27 (M+H).

Example 293N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxyphenyl)acetamido)methyl)phenyl)azetidine-1-carboxamidetrifluoroacetic acid salt

293A N-(3-Cyanophenyl)azetidine-1-carboxamide

293A was prepared from 3-cyanophenyl isocanate in 94% yield following aprocedure analogous to that used in the preparation of 287A. ¹H NMR (400MHz, CDCl₃) δ ppm 2.21-2.44 (m, 2H) 3.97-4.16 (m, 4H) 6.11 (s, 1H)7.21-7.29 (m, 1H) 7.34 (t, J=7.91 Hz, 1H) 7.62 (d, J=8.35 Hz, 1H) 7.75(s, 1H). LC-MS 202.34 (M+H).

293B N-(3-(Aminomethyl)phenyl)azetidine-1-carboxamide

293B was prepared from 293A in 59% yield following a procedure analogousto that used in the preparation of 288B. ¹H NMR (400 MHz, CD₃OD) δ ppm2.30 (t, J=7.69 Hz, 2H) 4.07 (m, 6H) 7.07 (d, J=5.71 Hz, 1H) 7.28-7.35(m, 2H) 7.63 (s, 1H). LC-MS 206.37 (M+H).

293C

Example 293 was prepared according to the general coupling-deprotectionprocedure using Intermediate 16 and 293B. ¹H NMR (400 MHz, CD₃OD) δ ppm1.35 (t, J=7.03 Hz, 3H) 2.20-2.36 (m, 2H) 3.97-4.06 (m, 6H) 4.25-4.48(m, 2H) 5.10 (s, 1H) 6.63 (d, J=2.20 Hz, 1H) 6.74 (d, J=7.03 Hz, 1H)6.78-6.83 (m, 1H) 6.89 (dd, J=8.35, 1.76 Hz, 1H) 7.06-7.12 (m, 3H) 7.16(dd, J=9.01, 2.42 Hz, 1H) 7.23-7.32 (m, 4H) 8.05 (d, J=9.23 Hz, 1H).LC-MS 525.29 (M+H).

Example 2942-(1-Aminoisoquinolin-6-ylamino)-N-(5-(3,3-dimethylureido)-2-(isopropylsulfonyl)benzyl)-2-(5-ethoxy-2-fluorophenyl)acetamidetrifluoroacetic acid salt

Example 294 was prepared according to the general coupling-deprotectionusing 73A and 290C. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.17 (d, J=7.03 Hz,3H) 1.20 (d, J=7.03 Hz, 3H) 1.27-1.35 (m, 3H) 3.01 (s, 6H) 3.37-3.47 (m,1H) 3.82-3.95 (m, 2H) 4.69 (dd, J=13.40, 5.93 Hz, 2H) 5.45 (s, 1H) 6.66(d, J=2.20 Hz, 1H) 6.78 (d, J=7.03 Hz, 1H) 6.85-6.91 (m, 1H) 6.92 (dd,J=5.71, 3.08 Hz, 1H) 7.08 (t, J=9.23 Hz, 1H) 7.14 (dd, J=9.23, 2.20 Hz,1H) 7.30 (d, J=7.47 Hz, 1H) 7.52 (dd, J=8.79, 2.20 Hz, 1H) 7.62 (d,J=2.20 Hz, 1H) 7.67 (d, J=8.79 Hz, 1H) 8.05 (d, J=9.23 Hz, 1H). LC-MS637.38 (M+H).

Example 295N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxyphenyl)acetamido)methyl)phenyl)thiazolidine-3-carboxamidetrifluoroacetic acid salt

295A N-(3-Cyanophenyl)thiazolidine-3-carboxamide

295A was prepared from 3-cyanophenyl isocanate in 87% yield following aprocedure analogous to that used in the preparation of 287A. ¹H NMR (400MHz, CDCl₃) δ ppm 3.13 (t, J=6.37 Hz, 2H) 3.83 (t, J=6.37 Hz, 2H) 4.60(s, 2H) 7.32 (d, J=3.08 Hz, 1H) 7.32-7.35 (m, 1H) 7.39 (t, J=7.91 Hz,1H) 7.70 (d, J=7.91 Hz, 1H) 7.81 (s, 1H). LC-MS 234.25 (M+H).

295B N-(3-(Aminomethyl)phenyl)thiazolidine-3-carboxamide

295A (200 mg, 0.86 mmol) was dissolved in 5 mL THF, BH₃ (4 mL, 1M inTHF, 4 mmol) was added, and the whole mixture was refluxed for 2 h, thenwas cooled down, HCl (5 mL, 1N) was added, the mixture was stirred 1 h.It was concentrated and purified by prep HPLC to provide 295B (220 mg)as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 3.11 (t, J=6.37 Hz, 2H)3.78 (t, J=6.37 Hz, 2H) 4.01-4.12 (m, 2H) 4.57 (s, 2H) 7.05-7.21 (m, 1H)7.28-7.43 (m, 2H) 7.58 (s, 1H). LC-MS 238.3 (M+H).

295C

Example 295 was prepared according to the general coupling-deprotectionusing Intermediate 16 and 295B. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.35 (t,J=6.81 Hz, 3H) 3.09 (t, J=6.15 Hz, 2H) 3.71-3.75 (m, 2H) 4.00 (q, J=7.03Hz, 2H) 4.36 (dd, J=7.91, 6.15 Hz, 2H) 4.52 (d, J=2.20 Hz, 2H) 5.10 (s,1H) 6.64 (d, J=2.20 Hz, 1H) 6.77 (d, J=7.03 Hz, 1H) 6.85 (d, J=7.47 Hz,1H) 6.89 (dd, J=8.13, 2.42 Hz, 1H) 7.11 (dd, J=13.62, 5.71 Hz, 3H) 7.17(dd, J=9.23, 2.20 Hz, 1H) 7.22-7.27 (m, 2H) 7.29 (s, 1H) 7.31 (s, 1H)8.06 (d, J=9.23 Hz, 1H). LC-MS 557.30 (M+H).

Example 296(R)-2-(1-Aminoisoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)-N-(5-(3,3-dimethylureido)-2-(isopropylsulfonyl)benzyl)acetamidetrifluoroacetic acid salt

296A(R)-2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)aceticacid

Intermediate 4 (10.5 g) was dissolved in 240 mL solvent (MeOH/TFA/DEA,100/0.1/0.05), and injected onto a Chiralpak AD column, eluted withCO₂/(MeOH/TFA/DEA, 100/0.1/0.05) (75/25). The first peak was collected.With 8 L solution in hand, Et₃N (4 mL) was added, and the whole wasconcentrated. The residue was mixed with CH₂Cl₂ (200 mL) and filtered,dried to provide 296A (2.8 g).

296B (R)-2-(1-Aminoisoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)aceticacid

Concentrated hydrochloric acid was added dropwise to a solution of 296A(366 mg, 1.04 mmol) in THF (10 mL), until a clear solution was obtained.The reaction mixture was concentrated and dried to provide 296B (402 mg)as a yellow solid. LC-MS 354.2 (M+H).

296C Example 296

296B (20 mg, 0.051 mmol), 290C (18.5 mg, 0.055 mmol), BOP (40 mg, 0.09mmol) and Et₃N (50 mg, 0.5 mmol) were mixed in DMF (2 mL), stirred at rtfor 2 h and purified by preperative HPLC to provide Example 296 (28.3mg) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.13 (d, J=7.03 Hz,3H) 1.16 (d, J=6.59 Hz, 3H) 3.00 (s, 6H) 3.33-3.43 (m, 1H) 3.74 (s, 3H)3.79 (s, 3H) 4.65-4.69 (m, 2H) 5.11 (s, 1H) 6.60 (d, J=2.20 Hz, 1H) 6.74(d, J=7.03 Hz, 1H) 6.92 (d, J=8.79 Hz, 1H) 7.02 (dd, J=9.01, 2.42 Hz,1H) 7.05-7.11 (m, 2H) 7.26 (d, J=7.03 Hz, 1H) 7.49 (dd, J=8.79, 2.20 Hz,1H) 7.56 (d, J=2.20 Hz, 1H) 7.66 (d, J=8.79 Hz, 1H) 7.95 (d, J=9.23 Hz,1H). LC-MS 635.32 (M+H).

Example 2972-(1-Aminoisoquinolin-6-ylamino)-2-(3-ethoxyphenyl)-N-(3-(3-isopropyl-3-methylureido)benzyl)acetamidetrifluoroacetic acid salt

297A 3-(3-Cyanophenyl)-1-isopropyl-1-methylurea

297A was prepared from 3-cyanophenyl isocanate in 89% yield following aprocedure analogous to that used in the preparation of 287A. ¹H NMR (400MHz, CDCl₃) δ ppm 1.16 (d, J=6.59 Hz, 6H) 2.86 (s, 3H) 4.50-4.63 (m, 1H)6.66 (s, 1H) 7.25-7.29 (m, 1H) 7.35 (t, J=7.91 Hz, 1H) 7.60-7.65 (m, 1H)7.79 (s, 1H). LC-MS 218.14 (M+H).

297B 3-(3-(Aminomethyl)phenyl)-1-isopropyl-1-methylurea

297B was prepared from 297A in 80% yield following a procedure analogousto that used in the preparation of 295B. ¹H NMR (400 MHz, CD₃OD) δ ppm1.1-8 (d, J=7.03 Hz, 6H) 2.87 (s, 3H) 4.05 (s, 2H) 4.48-4.59 (m, 1H)7.09 (d, J=6.59 Hz, 1H) 7.29-7.36 (m, 2H) 7.52 (s, 1H). LC-MS 222.26(M+H).

297C

Example 297 was prepared according to the general coupling-deprotectionusing Intermediate 16 and 297B. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.14 (s,3H) 1.35 (t, J=7.03 Hz, 3H) 2.83 (s, 3H) 3.99 (q, J=7.03 Hz, 2H) 4.35(dd, J=14.28-5.93 Hz, 2H) 4.45-4.5.5 (m, 1H) 5.12 (s, 1H) 6.65 (d,J=2.20 Hz, 1H) 6.77 (d, J=7.03 Hz, 1H) 6.82 (d, J=7.91 Hz, 1H) 6.88 (dd,J=8.35, 1.76 Hz, 1H) 7.07-7.14 (m, 3H) 7.16 (dd, J=9.23, 2.20 Hz, 1H)7.19-7.32 (m, 4H) 8.05 (d, J=9.23 Hz, 1H). LC-MS 541.35 (M+H).

Example 298(3S)—N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)acetamido)methyl)phenyl)-3-hydroxypyrrolidine-1-carboxamidetrifluoroacetic acid salt

298A 2-(1-Aminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)aceticacid

Intermediate 15 (350 mg, 0.61 mmol) was dissolved in EtOAc (12 mL). HCl(12 mL, 4N in dioxane) was added dropwise and the whole was stirred atrt overnight. The reaction mixture was concentrated and dried to provide298A (250 mg) as a yellow solid. LC-MS 372.1 (M+H).

298B (3S)—N-(3-Cyanophenyl)-3-hydroxypyrrolidine-1-carboxamide

298B was prepared from 3-cyanophenyl isocanate in 75% yield following aprocedure analogous to that used in the preparation of 287A. ¹H NMR (400MHz, CD₃OD) δ ppm 1.93-2.02 (m, 1H) 2.02-2.14 (m, 1H) 3.42-3.49 (m, 1 H)3.52-3.64 (m, 4-H) 4.45 (s, 1H) 7.30-7.35 (m, 1H) 7.70 (d, J=8.35 Hz,1H) 7.88 (d, J=2.20 Hz, 1H). LC-MS 232.12 (M+H).

298C (3S)—N-(3-(Aminomethyl)phenyl)-3-hydroxypyrrolidine-1-carboxamide

298C was prepared from 298B in 77% yield following a procedure analogousto that used in the preparation of 295B. ¹H NMR (400 MHz, CD₃OD) δ ppm1.93-2.02 (m, 1H) 2.03-2.14 (m, 1H) 3.43-3.51 (m, 1H) 3.52-3.64 (m, 4H)4.06 (s, 2H) 4.46 (s, 1H) 7.10 (d, J=6.59 Hz, 1H) 7.30-7.38 (m, 2H) 7.59(s, 1H). LC-MS 236.3 (M+H).

298D

Example 298 was prepared according to the general coupling procedureusing 298A and 298C. 298A (19 mg, 0.047 mmol), 298C (20 mg, 0.057 mmol),EDCI (20 mg, 0.1 mmol), HOAt (2 mg, 0.015 mmol), and DIEA (0.06 mL,0.345 mmol) were mixed in DMF (2 mL). The whole was stirred for 2 h at60° C. Purification through preparative HPLC provided Example 298 (13mg) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.38 (t, J=7.25 Hz,3H) 1.93-2.02 (m, 1H) 2.02-2.16 (m, 1H) 3.39-3.46 (m, 1H) 3.50-3.61 (m,4H) 4.03 (q, J=7.03 Hz, 2H) 4.36 (t, J=5.71 Hz, 2H) 4.43-4.49 (m, 1H)5.11-5.35 (m, 1H) 6.63-6.71 (m, 1H) 6.78 (d, J=7.03 Hz, 1H) 6.80-6.86(m, 1H) 7.06-7.22 (m, 4H) 7.23-7.39 (m, 4H) 8.06 (d, J=9.23 Hz, 1H).LC-MS 589.35 (M+H).

Example 299(3R)—N-(3-((2-(1-Aminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)acetamido)methyl)phenyl)-3-hydroxypyrrolidine-1-carboxamidetrifluoroacetic acid salt

299A (3R)—N-(3-Cyanophenyl)-3-hydroxypyrrolidine-1-carboxamide

299A was prepared from 3-cyanophenyl isocanate in 84% yield following aprocedure analogous to that used in the preparation of 287A. ¹H NMR (400MHz, CD₃OD) δ ppm 1.93-2.02 (m, 1H) 2.02-2.14 (m, 1H) 3.42-3.49 (m, 1H)3.53-3.62 (m, 4H) 4.42-4.49 (m, 1H) 7.30-7.34 (m, 1H) 7.41 (t, J=7.91Hz, 1H) 7.70 (d, J=8.35 Hz, 1H) 7.88 (d, J=2.20 Hz, 1H). LC-MS 232.14(M+H).

299B (3R)—N-(3-(aminomethyl)phenyl)-3-hydroxypyrrolidine-1-carboxamide

299B was prepared from 299A in 77% yield following a procedure analogousto that used in the preparation of 295B. ¹H NMR (400 MHz, CD₃OD) δ ppm1.94-2.02 (m, 1H) 2.02-2.14 (m, 1H) 3.43-3.49 (m, 1H) 3.53-3.63 (m, 4H)4.05 (s, 2H) 4.44-4.48 (m, 1H) 7.10 (d, J=6.59 Hz, 1H) 7.30-7.38 (m, 2H)7.58 (s, 1H). LC-MS 236.3 (M+H).

299C

Example 299 was prepared according to the general coupling procedureanalogous to that used in the preparation of Example 298 by using 298Aand 299B. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.37 (t, J=7.03 Hz, 3H)1.92-2.02 (m, 1H) 2.02-2.13 (m, 1H) 3.39-3.47 (m, 1H) 3.49-3.62 (m, 4H)4.03 (q, J=7.03 Hz, 2H) 4.32-4.39 (m, 2H) 4.43-4.48 (m, 1H) 5.14 (s, 1H)6.64 (d, J=2.20 Hz, 1-H) 6.77 (d, J=7.03 Hz, 1H) 6.83 (d, J=7.47 Hz, 1H)7.06-7.18 (m, 3H) 7.19 (d, J=2.20 Hz, 1H) 7.23-7.32 (m, 3H) 7.33-7.38(m, 1H) 8.02-8.09 (m, 1H). LC-MS 589.37 (M+H).

Example 3003-(1-(3,4-Dimethoxyphenyl)-2-(5-(3,3-dimethylureido)-2-(isopropylsulfonyl)benzylamino)-2-oxoethylamino)benzamidetrifluoroacetic acid salt

285A (24 mg, 0.05 mmol), 290C (18 mg, 0.054 mmol), BOP reagent (26 mg,0.06 mmol), and Et₃N (31 mg, 0.3 mmol) were mixed in DMF (1 mL) and thewhole mixture was stirred at rt for 1 h. Purification throughpreparative HPLC provided Example 300 (13 mg) of white solid. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.17 (d, J=3.95 Hz, 3H) 1.19 (d, J=3.52 Hz, 3H)3.01 (s, 6H) 3.34-3.44 (m, 1H) 3.73 (s, 3H) 3.78 (s, 3H) 4.67 (s, 2H)4.88 (s, 1H) 6.76-6.81 (m, 1H) 6.86-6.91 (m, 1H) 6.99-7.04 (m, 2H)7.11-7.19 (m, 3H) 7.48 (d, J=2.20 Hz, 1H) 7.53 (dd, J=8.79, 2.20 Hz, 1H)7.73 (d, J=8.79 Hz, 1H). LC-MS 612.3 (M+H).

UTILITY

The compounds of the present invention are inhibitors of factor VIIaand/or plasma kallirein and are useful as anticoagulants for theprevention or treatment of thromboembolic disorders in mammals. Ingeneral, a thromboembolic disorder is a circulatory disease caused byblood clots (i.e., diseases involving fibrin formation, plateletactivation, and/or platelet aggregation). The term “thromboembolicdisorders (or conditions)” as used herein includes arterial or venouscardiovascular or cerebovascular thromboembolic disorders, andthromboembolic disorders in the chambers of the heart or in theperipheral circulation. The term “thromboembolic disorders” as usedherein also includes specific disorders selected from, but not limitedto, unstable angina or other acute coronary syndromes, atrialfibrillation, first or recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, peripheralocclusive arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, cerebral embolism, kidney embolisms, pulmonary embolisms,and thrombosis resulting from medical implants, devices, or proceduresin which blood is exposed to an artificial surface that promotesthrombosis. The medical implants or devices include, but are not limitedto: prosthetic valves, artificial valves, indwelling catheters, stents,blood oxygenators, shunts, vascular access ports, and vessel grafts. Theprocedures include, but are not limited to: cardiopulmonary bypass,percutaneous coronary intervention, and hemodialysis.

It is noted that thrombosis includes vessel occlusion (e.g. after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy. The anticoagulant orantithrombotic effect of compounds of the present invention is believedto be due to inhibition of serine proteases involved in the coagulationcascade, more specifically, inhibition of the coagulation factors:factor VIIa, factor IXa, factor Xa, factor XIa, thrombin, and/or plasmakallikrein.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (p1. thrombi); clotting within a blood vessel which maycause ischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material which has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“stroke”, as used herein, refers to embolic stroke or atherothromboticstroke arising from occlusive thrombosis in the carotid communis,carotid interna, or intracerebral arteries.

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation factors VIIa, IXa, Xa, XIa, or thrombin, can bedetermined using a relevant purified serine protease, respectively, andan appropriate synthetic substrate. The rate of hydrolysis of thechromogenic substrate by the relevant serine protease was measured bothin the absence and presence of compounds of the present invention.Hydrolysis of the substrate resulted in the release of para-nitroaniline(pNA), which was monitored spectrophotometrically by measuring theincrease in absorbance at 405 nM, or the release of aminomethylcoumarin(AMC), which was monitored spectrofluorometrically by measuring theincrease in emission at 460 nM with excitation at 380 nM. A decrease inthe rate of absorbance change at 405 nM in the presence of inhibitor isindicative of enzyme inhibition. Such methods are known to one skilledin the art. The results of this assay are expressed as inhibitoryconstant, K_(i).

Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 Msodium chloride, 0.05 M HEPES buffer containing 0.5% PEG 8000 at a pH of7.4. Determinations were made using purified human Factor VIIa(Haematologic Technologies) or recombinant human Factor VIIa (NovoNordisk) at a final assay concentration of 2-5 nM, recombinant solubletissue factor at a concentration of 18-35 nM and the synthetic substrateH-D-Ile-Pro-Arg-pNA (S-2288; Chromogenix or BMPM-2; AnaSpec) at aconcentration of 0.001 M.

In general, preferred compounds of the present invention, such as theparticular compounds disclosed in the above examples, have beenidentified to be active and exhibit K_(i)'s of equal to or less than 15μM in the Factor VIIa assay, thereby demonstrating the utility of thecompounds of the present invention as especially effective inhibitors ofcoagulation Factor VIIa. More preferred compounds have K_(i)'s of equalto or less than 1 μM, preferably equal to or less than 0.5 μM, morepreferably equal to or less than 0.2 μM, even more preferably equal toor less than 0.1 μM.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 Msodium chloride, 0.05 M TRIS base and 0.5% PEG 8000 at a pH of 7.4.Determinations were made using purified human Factor IXa (HaematologicTechnologies) at a final assay concentration of 20-100 nM and thesynthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688(H-D-Leu-Phe-Gly-Arg-AMC; CenterChem) at a concentration of0.0004-0.0005 M. In general, compounds tested in the Factor IXa assayare considered to be active if they exhibit a K_(i) of equal to or lessthan 15 μM.

Factor Xa determinations were made in 0.1 M sodium phosphate buffer at apH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human Factor Xa (HaematologicTechnologies) at a final assay concentration of 150-1000 pM and thesynthetic substrate S-2222 (Bz-Ile-Glu(gamma-OMe, 50%)-Gly-Arg-pNA;Chromogenix) at a concentration of 0.0002-0.0003 M. In general,compounds tested in the Factor Xa assay are considered to be active ifthey exhibit a K_(i) of equal to or less than 15 μM.

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 75-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002-0.00025M. In general, compounds tested in the Factor XIa assay are consideredto be active if they exhibit a K_(i) of equal to or less than 15 μM.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 pM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002 M. Ingeneral, compounds tested in the thrombin assay are considered to beactive if they exhibit a K_(i) of equal to or less than 15 μM.

Plasma kallikrein determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human kallikrein (EnzymeResearch Laboratories) at a final assay concentration of 200 pM and thesynthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; Chromogenix) at aconcentration of 0.00008-0.0004 M. In general, compounds tested in theplasma kallikrein assay are considered to be active if they exhibit aK_(i) of equal to or less than 15 μM.

The selectivity of a compound may be evaluated by taking the ratio ofthe K_(i) value for a given protease with the K_(i) value for theprotease of interest (i.e., selectivity for FVIIa versus proteaseP=K_(i) for protease P/K_(i) for FVIIa). Compounds with selectivityratios >20 are considered selective. Compounds with selectivityratios >100 are preferred, and compounds with selectivity ratios >500are more preferred.

The Michaelis constant, K_(m), for substrate hydrolysis by each proteasewas determined at 25° C. using the method of Lineweaver and Burk. Valuesof K_(i) were determined by allowing the protease to react with thesubstrate in the presence of the inhibitor. Reactions were allowed to gofor periods of 20-180 minutes (depending on the protease) and thevelocities (rate of absorbance change vs time) were measured. Thefollowing relationship was used to calculate K_(i) values:(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m))) for a competitiveinhibitor with one binding site; orv _(s) /v _(o) =A+((B−A)/1+((IC ₅₀/(I)^(n)))) andK _(i) =IC ₅₀/(1+S/K _(m)) for a competitive inhibitor

where:

-   -   v_(o) is the velocity of the control in the absence of        inhibitor;    -   v_(s) is the velocity in the presence of inhibitor;    -   I is the concentration of inhibitor;    -   A is the minimum activity remaining (usually locked at zero);    -   B is the maximum activity remaining (usually locked at 1.0);    -   n is the Hill coefficient, a measure of the number and        cooperativity of potential inhibitor binding sites;    -   IC₅₀ is the concentration of inhibitor that produces 50%        inhibition under the assay conditions;    -   K_(i) is the dissociation constant of the enzyme:inhibitor        complex;    -   S is the concentration of substrate; and    -   K_(m) is the Michaelis constant for the substrate.

The effectiveness of compounds of the present invention asantithrombotic agents can be determined using relevant in vivothrombosis models, including In Vivo Electrically-induced Carotid ArteryThrombosis Models and In Vivo Rabbit Arterio-venous Shunt ThrombosisModels.

In Vivo Electrically-Induced Carotid Artery Thrombosis (ECAT) Model:

The rabbit ECAT model, described by Wong et al. (J. Pharmacol Exp Ther2000, 295, 212-218), can be used in this study. Male New Zealand Whiterabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM) andxylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics are supplemented asneeded. An electromagnetic flow probe is placed on a segment of anisolated carotid artery to monitor blood flow. Test agents or vehiclewill be given (i.v., i.p., s.c., or orally) prior to the initiation ofthrombosis. Thrombus formation is induced by electrical stimulation ofthe carotid artery for 3 min at 4 mA using an external stainless-steelbipolar electrode. Carotid blood flow is measured continuously over a90-min period to monitor thrombus-induced occlusion. Total carotid bloodflow over 90 min is calculated by trapezoidal rule. Average carotid flowover 90 min is then determined by converting total carotid blood flowover 90 min to percent of total control carotid blood flow, which wouldresult if control blood flow had been maintained continuously for 90min. The ED₅₀ (dose that increased average carotid blood flow over 90min to 50% of the control) of compounds are estimated by a nonlinearleast square regression program using the Hill sigmoid E_(max) equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

In Vivo Rabbit Arterio-Venous (AV) Shunt Thrombosis Model:

The rabbit AV shunt model, described by Wong et al. (Wong, P. C. et al.J Pharmacol Exp Ther 2000, 292, 351-357), can be used in this study.Male New Zealand White rabbits are anesthetized with ketamine (50mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). Theseanesthetics are supplemented as needed. The femoral artery, jugular veinand femoral vein are isolated and catheterized. A saline-filled AV shuntdevice is connected between the femoral arterial and the femoral venouscannulae. The AV shunt device consists of an outer piece of tygon tubing(length=8 cm; internal diameter=7.9 mm) and an inner piece of tubing(length=2.5 cm; internal diameter=4.8 mm). The AV shunt also contains an8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows fromthe femoral artery via the AV-shunt into the femoral vein. The exposureof flowing blood to a silk thread induces the formation of a significantthrombus. Forty minutes later, the shunt is disconnected and the silkthread covered with thrombus is weighed. Test agents or vehicle will begiven (i.v., i.p., s.c., or orally) prior to the opening of the AVshunt. The percentage inhibition of thrombus formation is determined foreach treatment group. The ID₅₀ values (dose which produces 50%inhibition of thrombus formation) are estimated by a nonlinear leastsquare regression program using the Hill sigmoid E_(max) equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. These otheragents include, but are not limited to, other anti-coagulant orcoagulation inhibitory agents, anti-platelet or platelet inhibitoryagents, or thrombolytic or fibrinolytic agents.

By “administered in combination” or “combination therapy” it is meantthat the compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin, heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin, for example LOVANOX™), syntheticpentasaccharide, direct acting thrombin inhibitors including hirudin andargatroban, as well as other factor VIIa inhibitors, factor IXainhibitors, factor Xa inhibitors (e.g., Arixtra™, apixaban, rivaroxaban,LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors, andinhibitors of activated TAFI and PAI-1 known in the art.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granular-content secretion ofplatelets. Such agents include, but are not limited to, the variousknown non-steroidal anti-inflammatory drugs (NSAIDS) such asacetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl,ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen,phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, andpharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS,aspirin (acetylsalicylic acid or ASA), and piroxicam are preferred.Other suitable platelet inhibitory agents include glycoprotein IIb/IIIaantagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin),thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III)inhibitors (e.g., dipyridamole, cilostazol), and PDE-V inhibitors (suchas sildenafil), protease-activated receptor 1 (PAR1) antagonists (e.g.,SCH-530348, SCH-203099, SCH-529153 and SCH-205831), and pharmaceuticallyacceptable salts or prodrugs thereof.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, is also intended to include ADP (adenosine diphosphate) receptorantagonists, preferably antagonists of the purinergic receptors P₂Y₁ andP₂Y₁₂, with P₂Y₁₂ being even more preferred. Preferred P₂Y₁₂ receptorantagonists include ticlopidine and clopidogrel, prasugrel, andAZD-6140, and pharmaceutically acceptable salts or prodrugs thereof.Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrelare also preferred compounds since they are known to be more gentle thanaspirin on the gastro-intestinal tract in use.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the secretion of platelet granule contents including and/orserotonin) and/or fibrin formation are disrupted. A number of thrombininhibitors are known to one of skill in the art and these inhibitors arecontemplated to be used in combination with the present compounds. Suchinhibitors include, but are not limited to, boroarginine derivatives,boropeptides, heparins, hirudin and argatroban, dabigatran, AZD-0837,and those disclosed in WO 98/37075 and WO 02/044145, andpharmaceutically acceptable salts and prodrugs thereof. Boroargininederivatives and boropeptides include N-acetyl and peptide derivatives ofboronic acid, such as C-terminal a-aminoboronic acid derivatives oflysine, ornithine, arginine, homoarginine and correspondingisothiouronium analogs thereof. The term hirudin, as used herein,includes suitable derivatives or analogs of hirudin, referred to hereinas hirulogs, such as disulfatohirudin.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa, andXIa, PAI-I inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmininhibitors, and anisoylated plasminogen streptokinase activator complex,including pharmaceutically acceptable salts or prodrugs thereof. Theterm anistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EuropeanPatent Application No. 028,489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable anti-arrythmic agents for use in combination withthe present compounds include: Class I agents (such as propafenone);Class II agents (such as carvadiol and propranolol); Class III agents(such as sotalol, dofetilide, amiodarone, azimilide and ibutilide);Class IV agents (such as ditiazem and verapamil); K⁺ channel openerssuch as I_(Ach) inhibitors, and I_(Kur) inhibitors (e.g., compounds suchas those disclosed in WO01/40231).

Examples of suitable antihypertensive agents for use in combination withthe compounds of the present invention include alpha adrenergicblockers; beta adrenergic blockers; calcium channel blockers (e.g.,diltiazem, verapamil, nifedipine, amlodipine and mybefradil); diruetics(e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, spironolactone); renin inhibitors;angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril,lisinopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), angiotensin AT-1 receptorantagonists (e.g., irbestatin, losartan, valsartan); ET-A receptorantagonists (e.g., sitaxsentan, atrsentan and compounds disclosed inU.S. Pat. Nos. 5,612,359 and 6,043,265); Dual ET-A/AT-1 antagonist(e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP)inhibitors; vasopepsidase inhibitors (dual ACE/NEP inhibitors, e.g.,omapatrilat gemopatrilat, nitrates) and β-blockers (for examplepropanolol, nadolo, or carvedilol).

Examples of suitable cardiac glycosides for use in combination with thecompounds of the present invention include digitalis and ouabain.

Examples of suitable mineralocorticoid receptor antagonists for use incombination with the compounds of the present invention includesprionolactone and eplirinone.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include: biguanides (e.g.,metformin); glucosidase inhibitors (e.g., acarbose); insulins (includinginsulin secretagogues or insulin sensitizers); meglitinides (e.g.,repaglinide); sulfonylureas (e.g., glimepiride, glyburide andglipizide); biguanide/glyburide combinations (e.g., glucovance),thiozolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone),PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dualagonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein(aP2) such as those disclosed in WO00/59506, glucagon-like peptide-1(GLP-1), and dipeptidyl peptidase IV (DPP4) inhibitors.

Examples of suitable anti-depressant agents for use in combination withthe compounds of the present invention include nefazodone andsertraline.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include: prednisone;dexamethasone; enbrel; protien tyrosine kinase (PTK) inhibitors;cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen;celecoxib; and/or rofecoxib.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate andraloxifene.

Examples of suitable hormone replacement therapies for use incombination with the compounds of the present invention include estrogen(e.g., congugated estrogens) and estradiol.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include orlistat, aP2 inhibitors(such as those disclosed in WO00/59506), and cannabinoid receptor CB1antagonists (e.g., rimonabant, AVE-1625, SR-147778, and CP-945598).

Examples of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, and hydroxyzine pamoate.

Examples of suitable anti-proliferative agents for use in combinationwith the compounds of the present invention include cyclosporin A,paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.

Cholesterol/lipid lowering agents for use in combination with thecompounds of the present invention include HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, fluvastatin, atorvsatatin,rosuvastatin, and other statins), sequestrants (cholestyramine andcolestipol), nicotonic acid, fenofibric acid derivatives (gemfibrozil,clofibrat, fenofibrate and benzafibrate), and probucol.

Examples of suitable anti-ulcer and gastroesophageal reflux diseaseagents for use in combination with the compounds of the presentinvention include famotidine, ranitidine, and omeprazole.

Administration of the compounds of the present invention (i.e., a firsttherapeutic agent) in combination with at least one additionaltherapeutic agent (i.e., a second therapeutic agent), preferably affordsan efficacy advantage over the compounds and agents alone, preferablywhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety. It is preferred that at least one of the therapeuticagents is administered in a sub-therapeutic dose. It is even morepreferred that all of the therapeutic agents be administered insub-therapeutic doses. Sub-therapeutic is intended to mean an amount ofa therapeutic agent that by itself does not give the desired therapeuticeffect for the condition or disease being treated. Synergisticcombination is intended to mean that the observed effect of thecombination is greater than the sum of the individual agentsadministered alone.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of plasma kallikrein, thrombin,factor VIIa, IXa, Xa and/or XIa. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving plasma kallikrein, thrombin, factor VIIa, IXa, Xa and/or XIa.For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimenter that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving plasma kallikrein, thrombin, factor VIIa, IXa, Xa,and/or XIa. For example, the presence of plasma kallikrein, thrombin,factor VIIa, IXa, Xa and/or XIa in an unknown sample could be determinedby addition of the relevant chromogenic substrate, for example, S2288for factor VIIa, to a series of solutions containing test sample andoptionally one of the compounds of the present invention. If productionof pNA is observed in the solutions containing test sample, but not inthe presence of a compound of the present invention, then one wouldconclude factor VIIa was present.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic disorder (as definedpreviously). In another embodiment, the package insert states that thepharmaceutical composition can be used in combination (as definedpreviously) with a second therapeutic agent to treat a thromboembolicdisorder. The article of manufacture can further comprise: (d) a secondcontainer, wherein components (a) and (b) are located within the secondcontainer and component (c) is located within or outside of the secondcontainer. Located within the first and second containers means that therespective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about0.001 to 20 mg/kg/day. Intravenously, the most preferred doses willrange from about 0.1 to about 10 mg/kg/minute during a constant rateinfusion. Compounds of this invention may be administered in a singledaily dose, or the total daily dosage may be administered in divideddoses of two, three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of the present invention and about 0.1 to7.5 milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 100 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 50milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to 25 milligrams of thecompound of the present invention and about 50 to 150 milligrams of theanti-platelet agent, preferably about 0.1 to 1 milligrams of thecompound of the present invention and about 1 to 3 milligrams ofantiplatelet agents, per kilogram of patient body weight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to 1 milligrams of the compound of the present invention, perkilogram of patient body weight and, in the case of the thrombolyticagents, the usual dosage of the thrombolyic agent when administeredalone may be reduced by about 50-80% when administered with a compoundof the present invention.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of the present invention, generally theamount of each component in a typical daily dosage and typical dosageform may be reduced relative to the usual dosage of the agent whenadministered alone, in view of the additive or synergistic effect of thetherapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

1. A compound of Formula (III):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: W is

X¹ is CH or N; R¹ is Cl, Br, Me, Et, OMe, OEt, OCHF₂, or cyclopropyl; R²is H, F, Cl, OMe, O(i-Pr), or OCHF₂; R³ is H or OMe; R⁴ is H, F, Cl, orOMe; R⁷ is H, Me, —CH₂CO₂H, or —CH₂CO₂(C₁₋₄ alkyl); R⁸ is H, Me, CO₂H,CO₂(C₁₋₄ alkyl), —CH₂CO₂H, or —CH₂CO₂(C₁₋₄ alkyl); R^(10a) is F, O(C₁₋₄alkyl), CONR^(c)R^(d), —S(C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl),—SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl,—SO₂-(pyrrolidin-1-yl), —SO₂-(piperid-1-yl), —SO₂-(azepan-1-yl),—SO₂NR^(c)R^(d), —SO₂NH-cyclopropyl, morpholin-4-yl,3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl; R^(10b) is OH,NH₂, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂NH₂, —SO₂NH₂, or—NHCONR^(c)R^(d); R^(10c) is H, Cl, or Me; R^(c) and R^(d) are,independently at each occurrence, H or C₁₋₄ alkyl; alternatively, R^(c)and R^(d), when attached to the same nitrogen atom, combine to form a 4-to 5-membered heterocycle comprising: carbon atoms and 0-2 additionalheteroatoms selected from N, O, and S(O)_(p); wherein said heterocycleis substituted with 0-2 R^(g); and R^(g) is, independently at eachoccurrence, ═O, F, Cl, Br, CF₃, OH, or C₁₋₄ alkyl.
 2. A compoundaccording to claim 1, wherein: W is

X¹ is CH; R⁷ is H, Me, or —CH₂CO₂H; R⁸ is H, Me, CO₂H, —CH₂CO₂H, or—CH₂CO₂Me; R^(10a) is F, O(i-Pr), —CONMe₂, —CO-(pyrrolidin-1-yl),—CO-(piperid-1-yl), —S(i-Pr), —SO₂Et, —SO₂Pr, —SO₂(i-Pr), —SO₂(t-Bu),—SO₂-cyclopropyl, —SO₂-cyclobutyl, —SO₂-cyclopentyl, —SO₂—(pyrrolidin-1-yl), —SO₂— (piperid-1-yl), —SO₂-(azepan-1-yl), —SO₂NHMe,—SO₂NMe₂, —SO₂NHEt, —SO₂NH(i-Pr), —SO₂NH-cyclopropyl, morpholin-4-yl,3,5-dimethyl-pyrazol-1-yl, or 3,5-diethyl-pyrazol-1-yl; R^(10b) is OH,NH₂, —NHCOMe, —NHCOPr, —NHCO₂Me, —NHCO₂Et, —NHCO₂(i-Pr), —NHCO₂(i-Bu),—NHSO₂NH₂, —SO₂NH₂, —NHCON(Me)₂, —NHCON(Me)(Et), —NHCON(Me)(i-Pr),

and R^(10c) is H.
 3. A method for treating a thromboembolic disorder,comprising: administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 4. A method according toclaim 3, wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, and thromboembolic disorders inthe chambers of the heart or in the peripheral circulation.
 5. A methodaccording to claim 3, wherein the thromboembolic disorder is selectedfrom unstable angina, an acute coronary syndrome, atrial fibrillation,first myocardial infarction, recurrent myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis.
 6. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim
 1. 7. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 2.8. A compound according to claim 1, wherein the compound is of Formula(IIIa):

or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim
 8. 10. Acompound according to claim 1, wherein the compound is selected from thegroup consisting of:

or a stereoisomer or a pharmaceutically acceptable salt thereof.
 11. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim10.